Machine learning discoveries of BCL-X synergy in ETC-1922159 treated colorectal cancer cells

Machine learning discoveries of BCL-X synergy in ETC-1922159 treated colorectal cancer cells shriprakash sinha Independent Researcher; Orcid ID : orcid.org/0000-0001-7027-5788 104-Madhurisha Heights Phase 1, Risali, Bhilai-490006, India Abstract Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regulated, individually. A recently developed search engine ranked combinations of BCL-X (X, a particular gene/protein) at 2nd order level after drug administration. These rankings reveal which BCL-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and determine the mechanism of functioning between the BCL and X. In this research work, we cover combinations of BCL with Interleukin (IL), Selenbp1, TP53, caspase (CASP), mucin (MUC) and exosome (EXOSC). Keywords: BCL, Porcupine inhibitor ETC-1922159, Sensitivity analysis, Colorectal cancer. 1. Introduction In the unpublished preprint Sinha [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Such combinations are of import due to the vast search space in which they exist and the difficulty to find them. The search engine facilitates in prioritizing the combinations5 as ranked biological hypotheses which the biologists might want to test in wet lab, to know if a synergistic combination is prevalent in a signaling pathway, in a direct or indirect manner. Interested readers are advised to go through unpublished preprints Sinha [1] and Sinha [2] for details regarding the search engine and the discoveries mentioned in there.10 IML dicoveries of BCL-X synergy in ETC-1922159 treated CRC cells Email address: sinha.shripra[email protected] (shriprakash sinha) 1Aspects of unpublished work were presented in a poster session at (1) the recently concluded first ever Wnt Gordon Conference, from 6-11 August 2017, held in Stowe, VT 05672, USA. Preprint submitted to Preprint August 31, 2024 2. Materials and Methods 2.1. Combinatorial search problem and a possible solution The issue of combinatorial search problem and a possible solution has been addressed in Sinha [3] and Sinha [2]. The details of the methodology of this manuscript have been explained in great detail in Sinha [3] & its application in Sinha [2]. Readers15 are requested to go through the same for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC1922159. In order to understand the significance of the solution proposed to the problem of combinatorial search that the biologists face in revealing unknown biological search problem, these works are of importance.20 Briefly, from Sinha [2], the pipleline works by computing sensitivity indicies for each of these unique combinations and then vectorising these indices to connote and form discriminative feature vector for each combination. Since each combination is unique, the training and the test data are same. In the training data, the combinations are arranged and ranks from 1 to n are assigned. The ranking algorithm then learns25 the patterns from these combinations/sensitivity index vectors. Next the learned model is used to rank the test data by generating the ranking score for each of the unique combination. Sorting these shuffled scores of test data leads to prioritization of the combinations. Joachims [4] show an example of applying learned model to training data (same as the test data) in https://www.cs.cornell.edu/people/tj/svm_30 light/svm_rank.html. Note that these combinations are now ranked and give the biologists a chance to narrow down their focus on crucial biological hypotheses in the form of combinations which the biologists might want to test. Analogous to the webpage search engine, where the click of a button for a few key-words leads to a ranked list of web links, the pipeline uses sensitivity indices as an indicator of the strength of35 the influence of factors or their combinations, as a criteria to rank the combinations. 3. Results & Discussion 3.1. BCL related synergies 3.1.1. Interleukin - BCL cross family analysis Qin et al. [5] observe that IL-6 inhibits starvation-induced autophagy via the STAT3/Bcl-40 2 signaling pathway. Gabellini et al. [6] observed that interleukin 8 mediates bcl-xLinduced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model. Guruprasath et al. [7] show taht interleukin-4 receptortargeted delivery of Bcl-xL siRNA sensitizes tumors to chemotherapy and inhibits tumor growth. Maraskovsky et al. [8] indicate that Bcl-2 can rescue T lymphocyte45 development in interleukin-7 receptor-deficient mice but not in mutant rag-1−/−mice. Akashi et al. [9] show that Bcl-2 rescues T lymphopoiesis in interleukin-7 receptordeficient mice. Interleukin-10 increases Bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells as shown by Weber-Nordt et al. [10]. Interleukin7 and interleukin-15 regulate the expression of thebcl-2 and c-myb genes in cutaneous50 2 T-cell lymphoma cells as shown by Qin et al. [11]. Bcl-2 is a negative regulator of interleukin-1βsecretion in murine macrophages in pharmacological-induced apoptosis as shown by Escandell et al. [12]. Alas et al. [13] observe that inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkins lymphoma to apoptosis. These findings indicate the synergy between55 BCL and Interleukin in different pathological cases. In CRC cells treated with ETC1922159, these were found to be up regulated. Tables 1 and 2 indicate the rankings of the IL and BCL family. On the left side is the rankings of IL w.r.t BCL family and the right side, the vice versa. We found IL-1A/1B/17C up regulated w.r.t BCL2L1. These are reflected in60 rankings of 2482 (laplace) and 1834 (rbf) for IL1A - BCL2L1; 2252 (laplace), 1920 (linear) for IL1B - BCL2L1; and 2481 (laplace), 2410 (linear) and 2512 (rbf) for IL17C - BCL2L1; IL-6ST/17REL were up regulated w.r.t BCL2L2. These are reflected in rankings of 2239 (laplace), 1927 (linear) and 2085 (rbf) for IL6ST - BCL2L2; and 2454 (laplace), 2510 (linear) and 2482 (rbf) for IL17REL - BCL2L2. IL-17REL were65 up regulated w.r.t BCL2L13. These are reflected in rankings of 2420 (laplace), 2419 (linear) and 2464 (rbf) for IL17REL - BCL2L13; IL-6ST/15RA were up regulated w.r.t BCL3. These are reflected in rankings of 1928 (laplace) and 2344 (rbf) for IL6ST - BCL3; and 2478 (laplace), 1820 (linear) and 2500 (rbf) for IL15RA - BCL3; IL1RAP/6ST/8/17REL were up regulated w.r.t BCL6. These are reflected in rankings70 of 2360 (linear) and 1813 (rbf) for IL1RAP - BCL6; 2419 (laplace) and 1962 (rbf) for IL6ST - BCL6; 2363 (laplace) and 2233 (linear) for IL8 - BCL6; and 2253 (laplace) and 2396 (linear) for IL17REL - BCL6; IL-1A/6ST/8/17REL were up regulated w.r.t BCL9L. These are reflected in rankings of 1932 (laplace) and 1942 (linear) for IL1A - BCL9L; 2249 (laplace) and 1960 (linear) for IL6ST - BCL9L; 2197 (linear) and 216275 (rbf) for IL8 - BCL9L; and 2308 (linear) and 1926 (rbf) for IL17REL - BCL9L; IL6ST/15RA were up regulated w.r.t BCL10. These are reflected in rankings of 2008 (laplace) and 1816 (rbf) for IL6ST - BCL10; and 2064 (linear) and 1789 (rbf) for IL15RA - BCL10; On the right side is the rankings of BCL w.r.t IL family. We found BCL2L1 up reg-80 ulated IL-1B/2RG/10RB. These are reflected in rankings of 1838 (laplace) and 2132 (rbf) for IL1B - BCL2L1; 2048 (laplace) and 1949 (rbf) for IL2RG - BCL2L1; and 1965 (linear) and 2024 (rbf) for IL10RB - BCL2L1; BCL2L2 was up regulated IL1A/1B/1RN/6ST/8/15/17C. These are reflected in rankings of 2407 (laplace), 2362 (linear) and 2464 (rbf) for IL1A - BCL2L2; 1807 (laplace), 2462 (linear) and 234485 (rbf) for IL1B - BCL2L2; 2298 (laplace) and 2092 (rbf) for IL1RN - BCL2L2; 2046 (linear) and 1859 (rbf) for IL6ST - BCL2L2; 1803 (laplace) and 2024 (rbf) for IL8 - BCL2L2; 2474 (laplace), 2142 (linear) and 2416 (rbf) for IL15 - BCL2L2; and 2512 (linear) and 2447 (rbf) for IL17C - BCL2L2; BCL2L13 was up regulated IL1RAP/1RN/2RG/6ST/8/10RB/15/15RA/17C. These are reflected in rankings of 245090 (linear) and 2510 (rbf) for IL1RAP - BCL2L13; 2503 (laplace) and 2378 (rbf) for IL1RN - BCL2L13; 2483 (laplace) and 2248 (rbf) for IL2RG - BCL2L13; 1899 (laplace), 2473 (linear) and 2046 (rbf) for IL6ST - BCL2L13; 2099 (laplace) and 2294 (rbf) for IL8 - BCL2L13; 2120 (laplace) and 1895 (linear) for IL10RB - BCL2L13; 2515 (laplace), 2160 (linear) and 2420 (rbf) for IL15 - BCL2L13; 1844 (linear) and 231895 (rbf) for IL15RA - BCL2L13; and 2004 (laplace), 2434 (linear) and 2500 (rbf) for 3 IL17C - BCL2L13; BCL3 was up regulated IL-8/10RB. These are reflected in rankings of 2266 (laplace) and 1983 (rbf) for IL8 - BCL3; and 2187 (laplace) and 2170 (rbf) for IL10RB - BCL3; 2298 (laplace); 2423 (linear) and 2294 (rbf) for IL1B - BCL6; 1919 (laplace) and 2301 (linear) for IL1RN - BCL6; 2106 (linear) and 2478 (rbf) for IL2RG100 - BCL6; 2123 (laplace), 2068 (linear) for IL8 - BCL6; 2084 (laplace), 1791 (linear) and 2203 (rbf) for IL15RA - BCL6; and for 1949 (linear) and 1930 (rbf) for IL17REL - BCL6; BCL10 was up regulated IL-1A/1RAP/1RN/2RG/10RB/15RA. These are reflected in rankings of 2405 (linear) and 1889 (rbf) for IL1A - BCL10; 1929 (laplace) and 2112 (rbf) for IL1RAP - BCL10; 1846 (laplace) and 1823 (linear) for IL1RN -105 BCL10; 1885 (laplace) and 1803 (linear) for IL2RG - BCL10; 2244 (laplace) and 2150 (linear) for IL10RB - BCL10; and 1810 (laplace) and 1835 (rbf) for IL15RA - BCL10; Finally, table 3 shows the derived influences which can be represented graphically, with the following influences - •IL w.r.t BCL with IL-1A/1B/17C <−BCL2L1; IL6ST/17REL <−BCL2L2; IL-17REL <−BCL2L13; IL-6ST/15RA <−BCL3; IL-110 1RAP/6ST/8/17REL <−BCL6; IL-1A/6ST/8/17REL <−BCL9L; and IL-6ST/15RA <−BCL10; •BCL w.r.t IL with IL-1B/2RG/10RB −>BCL2L1; IL-1A/1B/1RN/6ST/8/15/17C −>BCL2L2; IL-1RAP/1RN/2RG/6ST/8/10RB/15/15RA/17C −>BCL2L13; IL8/10RB −>BCL3; IL-1B/1RN/2RG/8/15RA/17REL −>BCL6; and IL-1A/1RAP/1RN/2RG/10RB/15RA −>BCL10;115 4 RANKING IL FAMILY VS BCL FAMILY RANKING OF IL FAMILY W.R.TBCL2L1 RANKING OF BCL2L1 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL2L1 2482 859 1834 IL1A - BCL2L1 780 1156 1712 IL1B - BCL2L1 2252 1920 1482 IL1B - BCL2L1 1838 954 2132 IL1RAP - BCL2L1 1128 815 1935 IL1RAP - BCL2L1 870 1777 1262 IL1RN - BCL2L1 648 2504 650 IL1RN - BCL2L1 973 385 1297 IL2RG - BCL2L1 1542 1439 700 IL2RG - BCL2L1 2048 486 1949 IL6ST - BCL2L1 663 553 1432 IL6ST - BCL2L1 284 674 468 IL8 - BCL2L1 260 202 2070 IL8 - BCL2L1 1430 1343 1417 IL10RB - BCL2L1 1867 347 17 IL10RB - BCL2L1 1659 1965 2024 IL15 - BCL2L1 1558 775 381 IL15 - BCL2L1 690 542 1277 IL15RA - BCL2L1 2136 1177 1533 IL15RA - BCL2L1 581 1107 972 IL17C - BCL2L1 2481 2410 2512 IL17C - BCL2L1 695 1739 1775 IL17REL - BCL2L1 815 657 374 IL17REL - BCL2L1 981 1225 509 RANKING OF IL FAMILY W.R.TBCL2L2 RANKING OF BCL2L2 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL2L2 138 361 86 IL1A - BCL2L2 2407 2362 2464 IL1B - BCL2L2 165 389 108 IL1B - BCL2L2 1807 2462 2344 IL1RAP - BCL2L2 623 1523 861 IL1RAP - BCL2L2 77 1897 1711 IL1RN - BCL2L2 2324 530 984 IL1RN - BCL2L2 2298 1620 2092 IL2RG - BCL2L2 2137 285 347 IL2RG - BCL2L2 2429 850 1744 IL6ST - BCL2L2 2239 1927 2085 IL6ST - BCL2L2 477 2046 1859 IL8 - BCL2L2 894 1418 1346 IL8 - BCL2L2 1803 1072 2024 IL10RB - BCL2L2 2243 738 1020 IL10RB - BCL2L2 1041 145 843 IL15 - BCL2L2 110 650 1347 IL15 - BCL2L2 2474 2142 2416 IL15RA - BCL2L2 258 1715 361 IL15RA - BCL2L2 1377 1211 2298 IL17C - BCL2L2 554 12 147 IL17C - BCL2L2 1168 2512 2447 IL17REL - BCL2L2 2454 2510 2482 IL17REL - BCL2L2 539 1875 1442 RANKING OF IL FAMILY W.R.TBCL2L13 RANKING OF BCL2L13 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL2L13 1572 458 174 IL1A - BCL2L13 1456 811 2403 IL1B - BCL2L13 927 227 424 IL1B - BCL2L13 1286 1446 2348 IL1RAP - BCL2L13 278 718 1941 IL1RAP - BCL2L13 823 2450 2510 IL1RN - BCL2L13 608 1277 881 IL1RN - BCL2L13 2503 623 2378 IL2RG - BCL2L13 507 1182 5 IL2RG - BCL2L13 2483 1648 2248 IL6ST - BCL2L13 1778 1403 246 IL6ST - BCL2L13 1899 2473 2046 IL8 - BCL2L13 178 468 1606 IL8 - BCL2L13 2099 910 2294 IL10RB - BCL2L13 991 1211 804 IL10RB - BCL2L13 2120 1895 194 IL15 - BCL2L13 1868 432 15 IL15 - BCL2L13 2515 2160 2420 IL15RA - BCL2L13 1629 2134 685 IL15RA - BCL2L13 933 1844 2318 IL17C - BCL2L13 995 84 20 IL17C - BCL2L13 2004 2434 2500 IL17REL - BCL2L13 2420 2419 2464 IL17REL - BCL2L13 1490 760 442 RANKING OF IL FAMILY W.R.TBCL3 RANKING OF BCL3 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL3 880 2462 396 IL1A - BCL3 474 436 1045 IL1B - BCL3 975 1507 40 IL1B - BCL3 799 303 926 IL1RAP - BCL3 1425 821 1129 IL1RAP - BCL3 44 164 1115 IL1RN - BCL3 149 471 311 IL1RN - BCL3 37 1784 477 IL2RG - BCL3 454 365 505 IL2RG - BCL3 524 2060 335 IL6ST - BCL3 1928 755 2344 IL6ST - BCL3 316 1457 607 IL8 - BCL3 1052 743 2044 IL8 - BCL3 2266 1236 1983 IL10RB - BCL3 95 800 1625 IL10RB - BCL3 2187 1600 2170 IL15 - BCL3 1041 820 214 IL15 - BCL3 17 966 182 IL15RA - BCL3 2478 1820 2500 IL15RA - BCL3 462 1476 1100 IL17C - BCL3 737 1682 8 IL17C - BCL3 1069 923 1926 IL17REL - BCL3 218 424 2019 IL17REL - BCL3 692 1897 1274 Table 1: 2nd order combinatorial hypotheses between BCL and IL 5 RANKING IL FAMILY VS BCL FAMILY RANKING OF IL FAMILY W.R.TBCL6 RANKING OF BCL6 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL6 157 5 1029 IL1A - BCL6 1034 2503 1669 IL1B - BCL6 274 767 1904 IL1B - BCL6 2298 2423 2294 IL1RAP - BCL6 1021 2360 1813 IL1RAP - BCL6 2403 1289 777 IL1RN - BCL6 2015 366 506 IL1RN - BCL6 1919 2301 1680 IL2RG - BCL6 425 553 480 IL2RG - BCL6 1389 2106 2478 IL6ST - BCL6 2419 1589 1962 IL6ST - BCL6 92 184 1752 IL8 - BCL6 2363 2233 1343 IL8 - BCL6 2123 2068 181 IL10RB - BCL6 853 383 1983 IL10RB - BCL6 847 1980 1186 IL15 - BCL6 500 397 1767 IL15 - BCL6 1297 1925 1014 IL15RA - BCL6 1686 1432 2269 IL15RA - BCL6 2084 1791 2203 IL17C - BCL6 227 255 2412 IL17C - BCL6 1349 1499 1321 IL17REL - BCL6 2253 2396 63 IL17REL - BCL6 38 1949 1930 RANKING OF IL FAMILY W.R.TBCL9L RANKING OF BCL9L W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL9L 1932 1942 210 IL1A - BCL9L 1620 1559 986 IL1B - BCL9L 1966 88 79 IL1B - BCL9L 361 1449 2484 IL1RAP - BCL9L 218 957 881 IL1RAP - BCL9L 984 623 1689 IL1RN - BCL9L 1629 937 132 IL1RN - BCL9L 689 55 1593 IL2RG - BCL9L 415 104 92 IL2RG - BCL9L 2113 892 567 IL6ST - BCL9L 2249 1960 1142 IL6ST - BCL9L 1718 1210 737 IL8 - BCL9L 814 2197 2162 IL8 - BCL9L 1679 1920 933 IL10RB - BCL9L 743 632 660 IL10RB - BCL9L 1631 717 1236 IL15 - BCL9L 1343 279 280 IL15 - BCL9L 568 1068 1794 IL15RA - BCL9L 1714 111 1279 IL15RA - BCL9L 206 951 251 IL17C - BCL9L 2029 196 94 IL17C - BCL9L 1031 573 1870 IL17REL - BCL9L 128 2308 1926 IL17REL - BCL9L 1214 1341 839 RANKING OF IL FAMILY W.R.TBCL10 RANKING OF BCL10 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - BCL10 5 1720 506 IL1A - BCL10 513 2405 1889 IL1B - BCL10 201 2404 803 IL1B - BCL10 2100 432 1251 IL1RAP - BCL10 1597 598 1869 IL1RAP - BCL10 1929 499 2112 IL1RN - BCL10 107 724 126 IL1RN - BCL10 1846 1823 209 IL2RG - BCL10 232 665 650 IL2RG - BCL10 1885 1803 1577 IL6ST - BCL10 2008 1698 1816 IL6ST - BCL10 451 71 337 IL8 - BCL10 1614 719 1555 IL8 - BCL10 204 1653 544 IL10RB - BCL10 2009 466 1053 IL10RB - BCL10 2244 2150 1578 IL15 - BCL10 35 2072 580 IL15 - BCL10 2174 1618 1375 IL15RA - BCL10 1477 2064 1789 IL15RA - BCL10 1810 1656 1835 IL17C - BCL10 8 2009 1232 IL17C - BCL10 705 1777 207 IL17REL - BCL10 2397 89 550 IL17REL - BCL10 839 1214 377 Table 2: 2nd order combinatorial hypotheses between BCL and IL 6 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t BCL IL-1A/1B/17C BCL2L1 IL-6ST/17REL BCL2L2 IL-17REL BCL2L13 IL-6ST/15RA BCL3 IL-1RAP/6ST/8/17REL BCL6 IL-1A/6ST/8/17REL BCL9L IL-6ST/15RA BCL10 BCL w.r.t IL IL-1B/2RG/10RB BCL2L1 IL-1A/1B/1RN/6ST/8/15/17C BCL2L2 IL-1RAP/1RN/2RG/6ST/8/10RB/15/15RA/17C BCL2L13 IL-8/10RB BCL3 IL-1B/1RN/2RG/8/15RA/17REL BCL6 IL-1A/1RAP/1RN/2RG/10RB/15RA BCL10 Table 3: 2nd order combinatorial hypotheses between IL and BCL family. 7 RANKING SELENBP1 VS BCL FAMILY RANKING OF BCL FAMILY W.R.TSELENBP1 RANKING OF SELENBP1 W.R.TBCL laplace linear rbf laplace linear rbf SELENBP1 - BCL2L12 2426 2033 2629 SELENBP1 - BCL2L12 2589 2195 2082 SELENBP1 - BCL6B 2446 2575 1956 SELENBP1 - BCL6B 182 110 494 SELENBP1 - BCL7A 2620 1326 2006 SELENBP1 - BCL7A 2015 1799 767 SELENBP1 - BCL9 2453 1568 1738 SELENBP1 - BCL9 2538 1916 1793 SELENBP1 - BCL11A 1921 2463 1566 SELENBP1 - BCL11A 905 931 401 SELENBP1 - BCL11B 1896 299 1385 SELENBP1 - BCL11B 2496 2636 2510 Table 4: 2nd order combinatorial hypotheses between BCL and SELENBP1 UNEXPLORED COMBINATORIAL HYPOTHESES SELENBP1 w.r.t BCL SELENBP1 BCL-9/11B BCL w.r.t SELENBP1 SELENBP1 BCL-6B/11A Table 5: 2nd order combinatorial hypotheses between SELENBP1 and BCL family. 3.1.2. Selenbp1 - BCL cross family analysis Deng et al. [14] study the effects of selenium on lead-induced alterations in Aβproduction and Bcl-2 family proteins. Yaming et al. [15] studied the effects of selenium dioxide on apoptosis, Bcl-2 and p53 expression, intracellular reactive oxygen species and calcium level in three human lung cancer cell lines. Activity of selenium on cell120 proliferation, cytotoxicity, and apoptosis and on the expression of CASP9, BCL-XL and APC in intestinal adenocarcinoma cells has been studied by Mauro et al. [16]. These studies suggest the synergy between BCL and Selenium based genes. In CRC cells treated with ETC-1922159, these were found to be down regulated. Table 4 shows the rankings of BCL family w.r.t to SELENBP1 and vice versa.125 On the right side, we found BCL-6B/11A to be up regulated with respect to SELENBP1. These were reflected in the rankings of 182 (laplace), 110 (linear) and 494 (rbf) for SELENBP1 - BCL6B; and 905 (laplace), 931 (linear) and 401 (rbf) for SELENBP1 - BCL11A. On the left side SELENBP1 was up regulated w.r.t BCL-9/11B. These are reflected in rankings of 1568 (linear) and 1738 (rbf) for SELENBP1 - BCL9;130 and 299 (linear) and 1385 (rbf) for SELENBP1 - BCL11B; Finally, table 5 shows the derived influences which can be represented graphically, with the following influences -•SELENBP1 w.r.t BCL with SELENBP1 <−BCL-9/11B; and •BCL w.r.t SELENBP1 with SELENBP1 −>BCL-6B/11A; 8 3.1.3. TP53 - BCL cross family analysis135 The p53-Bcl-2 connection has been studied by Hemann and Lowe [17]. Tomita et al. [18] show wild type p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. Bcl-2 constitutively suppresses p53-dependent apoptosis in colorectal cancer cells as shown by Jiang and Milner [19]. The tissue dependent interactions between p53 and Bcl-2 in vivo has been140 studied by Li et al. [20]. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML has been studied by Pan et al. [21]. Zaidi et al. [22] observe that the chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent. Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas has been studied in Wilson et al. [23].145 TP53 and BCL family members were found to be up regulated in CRC cells treated with ETC-1922159. Table 6 show rankings of BCL and TP53 family w.r.t to each other. On the left side, we found BCL2L2 to be up regulated w.r.t TP53-I3/INP2. These are reflected in the rankings of 2423 (laplace), 2377 (linear) and 2452 (rbf) for TP53I3150 - BCL2L2; 1827 (linear) and 2035 (rbf) for TP53INP2 - BCL2L2. BCL2L13 to be up regulated w.r.t TP53-INP2. These are reflected in the rankings of 2427 (linear) and 2008 (rbf) for TP53INP2 - BCL2L13; BCL6 to be up regulated w.r.t TP53-I3/INP2. These are reflected in the rankings of 2275 (laplace), 2312 (linear) and 2146 (rbf) for TP53I3 - BCL6; and 2329 (linear) and 2352 (rbf) for TP53INP2 - BCL6; BCL9L to be155 up regulated w.r.t TP53-BP2. These are reflected in the rankings of 2320 (linear) and 2197 (rbf) for TP53BP2 - BCL9L; BCL10 to be up regulated w.r.t TP53-BP2/INP2. These are reflected in the rankings of 2230 (laplace) and 2418 (linear) for TP53BP2 - BCL10 and 1910 (linear) and 2087 (rbf) for TP53INP2 - BCL10; On the right side, we found TP53-BP2/I3 to be up regulated w.r.t BCL2L1. These160 are reflected in the rankings of 1786 (laplace) and 1961 (linear) for TP53BP2 - BCL2L1; 1980 (laplace) and 1752 (linear) for TP53I3 - BCL2L1; TP53-INP1 were up regulated w.r.t BCL3. These are reflected in the rankings for 2259 (linear) and 2043 (rbf) for TP53INP1 - BCL3; TP53-BP2/INP2 were up regulated w.r.t BCL9L. These are reflected in the rankings for 2093 (laplace) and 2217 (linear) for TP53BP2 - BCL9L; and165 2222 (laplace) and 1900 (linear) for TP53INP2 - BCL9L; Finally, table 7 shows the derived influences which can be represented graphically, with the following influences - •BCL w.r.t TP53 with TP53-I3/INP2 <−BCL2L2; TP53-INP2 <−BCL2L13; TP53-I3/INP2 <−BCL6; TP53-BP2 <−BCL9L; and TP53-BP2/INP2 <−BCL10; •TP53 w.r.t BCL with TP53-BP2/I3 <−BCL2L1;170 TP53-INP1 <−BCL3 and TP53-BP2/INP2 <−BCL9L. 9 RANKING MUC FAMILY VS BCL FAMILY RANKING OF BCL2L1 W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL2L1 laplace linear rbf laplace linear rbf MUC1 - BCL2L1 2055 2297 1854 MUC1 - BCL2L1 1226 1681 986 MUC3A - BCL2L1 603 2089 1637 MUC3A - BCL2L1 759 1107 678 MUC4 - BCL2L1 531 1137 711 MUC4 - BCL2L1 1758 999 487 MUC12 - BCL2L1 882 810 1305 MUC12 - BCL2L1 1591 900 272 MUC13 - BCL2L1 1927 1201 2108 MUC13 - BCL2L1 98 2160 1099 MUC17 - BCL2L1 1170 917 743 MUC17 - BCL2L1 2500 93 148 MUC20 - BCL2L1 1810 700 1627 MUC20 - BCL2L1 270 343 423 RANKING OF BCL2L2 W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL2L2 laplace linear rbf laplace linear rbf MUC1 - BCL2L2 1578 1425 1826 MUC1 - BCL2L2 2476 903 739 MUC3A - BCL2L2 1542 370 159 MUC3A - BCL2L2 2099 241 2397 MUC4 - BCL2L2 1323 2506 1988 MUC4 - BCL2L2 797 727 851 MUC12 - BCL2L2 602 2504 815 MUC12 - BCL2L2 516 38 1688 MUC13 - BCL2L2 2084 2402 1200 MUC13 - BCL2L2 2201 717 233 MUC17 - BCL2L2 2283 2212 1279 MUC17 - BCL2L2 903 295 913 MUC20 - BCL2L2 890 1886 480 MUC20 - BCL2L2 1892 569 1040 RANKING OF BCL2L13 W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL2L13 laplace linear rbf laplace linear rbf MUC1 - BCL2L13 2029 2347 550 MUC1 - BCL2L13 1838 903 739 MUC3A - BCL2L13 2140 1123 1100 MUC3A - BCL2L13 173 241 2397 MUC4 - BCL2L13 1497 1918 1579 MUC4 - BCL2L13 1906 727 851 MUC12 - BCL2L13 581 2353 1997 MUC12 - BCL2L13 2096 38 1688 MUC13 - BCL2L13 1210 2185 1658 MUC13 - BCL2L13 1688 717 233 MUC17 - BCL2L13 1079 1270 1254 MUC17 - BCL2L13 1167 295 913 MUC20 - BCL2L13 187 2081 535 MUC20 - BCL2L13 1653 569 1040 RANKING OF BCL3 W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL3 laplace linear rbf laplace linear rbf MUC1 - BCL3 458 1016 1881 MUC1 - BCL3 273 360 1683 MUC3A - BCL3 1642 668 588 MUC3A - BCL3 1044 860 1452 MUC4 - BCL3 427 321 457 MUC4 - BCL3 624 1360 585 MUC12 - BCL3 1813 311 1623 MUC12 - BCL3 1193 1092 132 MUC13 - BCL3 2151 641 1407 MUC13 - BCL3 279 65 603 MUC17 - BCL3 1106 531 2310 MUC17 - BCL3 305 1285 257 MUC20 - BCL3 2512 63 2440 MUC20 - BCL3 16 539 2198 RANKING OF BCL6 W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL6 laplace linear rbf laplace linear rbf MUC1 - BCL6 1652 2294 173 MUC1 - BCL6 1550 595 788 MUC3A - BCL6 2323 1435 187 MUC3A - BCL6 407 809 318 MUC4 - BCL6 723 711 1403 MUC4 - BCL6 176 203 1963 MUC12 - BCL6 184 1024 1267 MUC12 - BCL6 1126 26 229 MUC13 - BCL6 158 1083 2198 MUC13 - BCL6 1633 1052 603 MUC17 - BCL6 2411 2153 1808 MUC17 - BCL6 242 719 1026 MUC20 - BCL6 925 840 2153 MUC20 - BCL6 1132 1669 652 RANKING OF BCL9L W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL9L laplace linear rbf laplace linear rbf MUC1 - BCL9L 2194 744 1112 MUC1 - BCL9L 1144 1999 896 MUC3A - BCL9L 2114 1441 1359 MUC3A - BCL9L 901 2180 2106 MUC4 - BCL9L 882 466 1526 MUC4 - BCL9L 658 1152 781 MUC12 - BCL9L 1547 526 2391 MUC12 - BCL9L 1733 1510 366 MUC13 - BCL9L 1545 1891 796 MUC13 - BCL9L 1529 502 602 MUC17 - BCL9L 1282 1160 1362 MUC17 - BCL9L 955 1788 99 MUC20 - BCL9L 2101 116 2408 MUC20 - BCL9L 307 1516 1042 RANKING OF BCL10 W.R.TMUC FAMILY RANKING OF MUC FAMILY W.R.TBCL10 laplace linear rbf laplace linear rbf MUC1 - BCL10 1325 1524 1900 MUC1 - BCL10 547 1319 284 MUC3A - BCL10 1298 1004 1509 MUC3A - BCL10 1681 751 2250 MUC4 - BCL10 304 1632 1050 MUC4 - BCL10 591 570 151 MUC12 - BCL10 1019 1093 2239 MUC12 - BCL10 38 1155 817 MUC13 - BCL10 358 1687 2004 MUC13 - BCL10 517 2229 455 MUC17 - BCL10 524 2038 1579 MUC17 - BCL10 216 803 132 MUC20 - BCL10 1380 619 2081 MUC20 - BCL10 97 465 239 Table 10: 2nd order combinatorial hypotheses between BCL and SELENBP1 16 UNEXPLORED COMBINATORIAL HYPOTHESES MUC w.r.t BCL MUC-3A BCL2L2 MUC-3A BCL9L BCL w.r.t MUC MUC-1/13 BCL2L1 MUC-4/13/17 BCL2L2 MUC-1/12 BCL2L13 MUC-20 BCL3 MUC-17 BCL6 MUC-20 BCL9L Table 11: 2nd order combinatorial hypotheses between MUC and BCL family. 17 3.1.6. EXOSC - BCL cross family analysis The exosome complex is involved in the degradation of various kinds of RNA. Recently, Deng et al. [30] observe that Exosome-transmitted LINC00461 promotes multiple myeloma cell proliferation and suppresses apoptosis by modulating microRNA/BCL-230 2 expression. Xu et al. [31] show that Exosome-derived microRNA-29c induces apoptosis of BIU-87 cells by down regulating BCL-2 and MCL-1. Exosomes were demonstrated to upregulate the expression of Bcl-2 and Cyclin D1 proteins, but reduce the levels of Bax and caspase-3 proteins in these cells in work of Yang et al. [32]. In western blot analysis results showed that exosomes can block the significant reduction235 of BCL-2, full-length caspase-3 and full-length PARP, while preventing the increase of BAX, cleaved caspase-3 and cleaved PARP induced by VP16, as studied by Wang et al. [33]. These findings point to the definite synergistic role of exosome with BCL family. In CRC cells, both exosome components EXOSC and BCL family members were found to be down regulated, after ETC-1922159 drug treatment. The search engine240 allocated low numerical valued ranks for many of the EXOSC and BCL combinations which might suggest greater role of EXOSC along with BCL. However, the nature of the mechanism between the two families yet needs to be explored, despite the generated hypothesis of possible synergy. Table 12 shows rankings of EXOSC and BCL family with respect to each other.245 Left half of the table shows rankings of EXOSC w.r.t BCL and right half shows the vice versa. On the left, we find EXOSC2 to be down regulated w.r.t BCL-2L12/6B/7A/9/11A/11B. These are shown in the rankings of 723 (laplace), 355 (linear) and 1211 (rbf) for EXOSC2 - BCL2L12; 1092 (laplace), 1033 (linear) and 638 (rbf) for EXOSC2 - BCL6; 1633 (laplace), 1047 (linear) and 317 (rbf) for EXOSC2 - BCL7A; 699 (laplace), 559250 (linear) and 425 (rbf) for EXOSC2 - BCL9; 338 (laplace), 319 (linear) and 1598 (rbf) for EXOSC2 - BCL11A; and 1285 (laplace), 1440 (linear) and 812 (rbf) for EXOSC2 - BCL11B; EXOSC3 was found to down regulated w.r.t BCL11B. This is reflected in rankigns of 1677 (laplace), 199 (linear) and 267 (rbf) for EXOSC3 - BCL11B. EXOSC5 was found to be down regulated w.r.t BCL family. These are reflected in the255 rankings of 498 (laplace), 1342 (linear) and 436 (rbf) for EXOSC5 - BCL2L12; 786 (laplace), 1272 (linear) and 1194 (rbf) for EXOSC5 - BCL6B; 374 (laplace), 1338 (linear) and 874 (rbf) for EXOSC5 - BCL7A; 613 (laplace), 946 (linear) and 772 (rbf) for EXOSC5 - BCL9; 459 (laplace), 90 (linear) and 1034 (rbf) for EXOSC5 - BCL11A; and 1404 (laplace) and 1558 (linear) for EXOSC5 - BCL11B; EXOSC6 was found to260 be down regulated w.r.t BCL family. These are reflected in rankings of 1676 (laplace), 787 (linear) and 944 (rbf) for EXOSC6 - BCL7A; 1059 (linear) and 1091 (rbf) for EXOSC6 - BCL9; 1677 (laplace) and 1573 (linear) for EXOSC6 - BCL11A; EXOSC7 was found to be down regulated w.r.t BCL family. These are reflected in rankings of 666 (laplace); 98 (linear) and 743 (rbf) EXOSC7 - BCL6B; 1501 (linear) and 1513 (rbf)265 for EXOSC7 - BCL7A; and 1477 (laplace) and 1217 (rbf) for EXOSC7 - BCL11A; EXOSC8 was found to be down regulated w.r.t BCL family. Thesea reflected in 1175 (laplace), 1504 (linear) and 1743 (rbf) for EXOSC8 - BCL7A; 906 (linear) and 1130 (rbf) EXOSC8 - BCL11A; and 605 (linear) and 374 (rbf) for EXOSC8 - BCL11B; EXOSC9 found to be down regulate w.r.t BCL family. These are reflected in rankings270 of 1179 (laplace); 1018 (linear) and 687 (rbf) for EXOSC9 - BCL2L12; 437 (laplace), 18 852 (linear) and 1358 (rbf) EXOSC9 - BCL6B; 821 (laplace), 346 (linear) and 727 (rbf) for EXOSC9 - BCL7A; 1305 (laplace) and 299 (rbf) EXOSC9 - BCL9; 1569 (laplace), 549 (linear) and 1456 (rbf) for EXOSC9 - BCL11B. On the right, we find BCL-6B/11A/11B to be down regulated w.r.t EXOSC2. These275 are reflected in the rankings of 202 (laplace), 81 (linear) and 194 (rbf) for EXOSC2 - BCL6B; 574 (laplace), 834 (linear) and 1055 (rbf) for EXOSC2 - BCL11A; and 1368 (laplace), 1353 (linear) and 1455 (rbf) for EXOSC2 - BCL11B. BCL-6B/7A/11A was found to be down regulated w.r.t EXOSC3. These are reflected in rankings of 571 (laplace), 335 (linear) and 307 (rbf) for EXOSC3 - BCL6B; 1739 (laplace) and 1700280 (rbf) for EXOSC3 - BCL7A; and 1018 (laplace), 1345 (linear) and 483 (rbf) for EXOSC3 - BCL11A; BCL-6B/11A/11B was found to be down regulated w.r.t EXOSC5. These were reflected in rankings of 571 (laplace), 335 (linear) and 307 (rbf) for EXOSC5 - BCL6B; 756 (laplace), 389 (linear) and 1183 (rbf) for EXOSC5 - BCL11A; and 1368 (laplace), 1353 (linear) and 1455 (rbf) for EXOSC5 - BCL11B. BCL-9 was found285 to be down regulated w.r.t EXOSC6. These are reflected in rankigns of 851 (linear) and 1564 (rbf) for EXOSC6 - BCL9. BCL-2L12/7A/9/11A/11B was found to be down regulated w.r.t EXOSC7. These are reflected in rankings of 1551 (linear) and 1099 (rbf) for EXOSC7 - BCL2L12; 1282 (laplace), 831 (linear) and 1218 (rbf) for EXOSC7 - BCL7A; 1234 (linear) and 328 (rbf) for EXOSC7 - BCL9; 520 (laplace), 117 (linear)290 and 686 (rbf) for EXOSC7 - BCL11A; and 1529 (laplace) and 1418 (rbf) for EXOSC7 - BCL11B; BCL-6B/11A was found to be down regulated with EXOSC8. These are reflected in rankings of 190 (laplace), 1630 (linear) and 472 (rbf) for EXOSC8 - BCL6B; and 944 (laplace) and 532 (rbf) for EXOSC8 - BCL11A. Finally, BCL-6B/9/11A/11B was found to be down regulated with EXOSC9. These are reflected in rankings of 634295 (laplace), 304 (linear) and 146 (rbf) for EXOSC9 - BCL6B; 1197 (laplace) and 1279 (rbf) for EXOSC9 - BCL9; 481 (laplace), 441 (linear) and 1372 (rbf) for EXOSC9 - BCL11A; and 1454 (linear) and 133 (rbf) for EXOSC9 - BCL11B. Table 13 shows the derived influences which can be represented graphically, with the following influences - •EXOSC w.r.t BCL with EXOSC2 <−BCL-2L12/6B/7A/9/11A/11B;300 EXOSC3 <−BCL-11B; EXOSC5 <−BCL-2L12/6B/7A/9/11A/11B; EXOSC6 <− BCL-7A/9/11A; EXOSC7 <−BCL-6B/7A/11A; EXOSC8 <−BCL-7A/11A/11B and EXOSC9 <−BCL-2L12/6B/7A/9/11B; and •BCL w.r.t EXOSC with EXOSC2 −>BCL-6B/11A/11B; EXOSC3 −>BCL-6B/7A/11A; EXOSC5 −>BCL-6B/11A/11B; EXOSC6 -¿ BCL-2L12/9; EXOSC7 −>BCL-2L12/7A/9/11A/11B; EXOSC8 −>305 BCL-6B/11A and EXOSC9 −>BCL-6B/9/11A/11B. 19 RANKING EXOSC FAMILY VS BCL FAMILY RANKING OF EXOSC2 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC2 laplace linear rbf laplace linear rbf EXOSC2 - BCL2L12 723 355 1211 EXOSC2 - BCL2L12 1498 1889 1856 EXOSC2 - BCL6B 1092 1033 638 EXOSC2 - BCL6B 202 81 194 EXOSC2 - BCL7A 1633 1047 317 EXOSC2 - BCL7A 2403 2531 2405 EXOSC2 - BCL9 699 559 425 EXOSC2 - BCL9 2552 2230 1755 EXOSC2 - BCL11A 338 319 1598 EXOSC2 - BCL11A 574 834 1055 EXOSC2 - BCL11B 1285 1440 812 EXOSC2 - BCL11B 1067 1574 730 RANKING OF EXOSC3 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC3 laplace linear rbf laplace linear rbf EXOSC3 - BCL2L12 2280 1640 1955 EXOSC3 - BCL2L12 1976 1482 2399 EXOSC3 - BCL6B 2429 2273 2407 EXOSC3 - BCL6B 571 335 307 EXOSC3 - BCL7A 2100 1374 2674 EXOSC3 - BCL7A 1739 1882 1700 EXOSC3 - BCL9 2437 2223 2245 EXOSC3 - BCL9 2380 1912 2321 EXOSC3 - BCL11A 2212 2090 116 EXOSC3 - BCL11A 1018 1345 483 EXOSC3 - BCL11B 1677 199 267 EXOSC3 - BCL11B 2572 1876 2395 RANKING OF EXOSC5 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC5 laplace linear rbf laplace linear rbf EXOSC5 - BCL2L12 498 1342 436 EXOSC5 - BCL2L12 2174 1635 1824 EXOSC5 - BCL6B 786 1272 1194 EXOSC5 - BCL6B 330 193 107 EXOSC5 - BCL7A 374 1338 874 EXOSC5 - BCL7A 2582 2701 2415 EXOSC5 - BCL9 613 946 772 EXOSC5 - BCL9 1777 1511 2011 EXOSC5 - BCL11A 459 90 1034 EXOSC5 - BCL11A 756 389 1183 EXOSC5 - BCL11B 1404 2520 1558 EXOSC5 - BCL11B 1368 1353 1455 RANKING OF EXOSC6 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC6 laplace linear rbf laplace linear rbf EXOSC6 - BCL2L12 1327 1857 2063 EXOSC6 - BCL2L12 2268 1527 478 EXOSC6 - BCL6B 1965 2525 1825 EXOSC6 - BCL6B 18 2334 2512 EXOSC6 - BCL7A 1676 787 944 EXOSC6 - BCL7A 593 2653 2037 EXOSC6 - BCL9 1838 1059 1091 EXOSC6 - BCL9 1846 851 1564 EXOSC6 - BCL11A 1677 1573 2217 EXOSC6 - BCL11A 596 2307 2547 EXOSC6 - BCL11B 1897 1736 1126 EXOSC6 - BCL11B 2094 2223 81 RANKING OF EXOSC7 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC7 laplace linear rbf laplace linear rbf EXOSC7 - BCL2L12 1899 1755 974 EXOSC7 - BCL2L12 1721 1551 1099 EXOSC7 - BCL6B 666 98 743 EXOSC7 - BCL6B 2730 2690 2689 EXOSC7 - BCL7A 2290 1501 1513 EXOSC7 - BCL7A 1282 831 1218 EXOSC7 - BCL9 2363 1134 2219 EXOSC7 - BCL9 1845 1234 328 EXOSC7 - BCL11A 1477 2239 1217 EXOSC7 - BCL11A 520 117 686 EXOSC7 - BCL11B 2396 1524 2037 EXOSC7 - BCL11B 1529 2720 1418 RANKING OF EXOSC8 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC8 laplace linear rbf laplace linear rbf EXOSC8 - BCL2L12 2042 2152 506 EXOSC8 - BCL2L12 1967 1525 2275 EXOSC8 - BCL6B 2469 2134 2224 EXOSC8 - BCL6B 190 1630 472 EXOSC8 - BCL7A 1175 1504 1743 EXOSC8 - BCL7A 2065 2351 1069 EXOSC8 - BCL9 1733 2452 1164 EXOSC8 - BCL9 2640 1895 1747 EXOSC8 - BCL11A 1864 906 1130 EXOSC8 - BCL11A 944 2303 532 EXOSC8 - BCL11B 1547 605 374 EXOSC8 - BCL11B 2581 2728 2359 RANKING OF EXOSC9 W.R.TBCL FAMILY RANKING OF BCL FAMILY W.R.TEXOSC9 laplace linear rbf laplace linear rbf EXOSC9 - BCL2L12 1179 1018 687 EXOSC9 - BCL2L12 2105 1762 1453 EXOSC9 - BCL6B 437 852 1358 EXOSC9 - BCL6B 634 304 146 EXOSC9 - BCL7A 821 346 727 EXOSC9 - BCL7A 985 2017 2207 EXOSC9 - BCL9 1305 1849 299 EXOSC9 - BCL9 1197 1279 2154 EXOSC9 - BCL11A 892 2426 2011 EXOSC9 - BCL11A 481 441 1372 EXOSC9 - BCL11B 1569 549 1456 EXOSC9 - BCL11B 2606 1454 133 Table 12: 2nd order combinatorial hypotheses between BCL and EXOSC 20 UNEXPLORED COMBINATORIAL HYPOTHESES EXOSC w.r.t BCL EXOSC2 BCL-2L12/6B/7A/9/11A/11B EXOSC3 BCL-11B EXOSC5 BCL-2L12/6B/7A/9/11A/11B EXOSC6 BCL-7A/9/11A EXOSC7 BCL-6B/7A/11A EXOSC8 BCL-7A/11A/11B EXOSC9 BCL-2L12/6B/7A/9/11B BCL w.r.t EXOSC EXOSC2 BCL-6B/11A/11B EXOSC3 BCL-6B/7A/11A EXOSC5 BCL-6B/11A/11B EXOSC6 BCL-2L12/9 EXOSC7 BCL-2L12/7A/9/11A/11B EXOSC8 BCL-6B/11A EXOSC9 BCL-6B/9/11A/11B Table 13: 2nd order combinatorial hypotheses between EXOSC and BCL family. 21 Conclusion Presented here are a range of multiple synergistic BCL 2nd order combinations that were ranked via a search engine. Later, two way cross family analysis between components of these combinations were conducted. Via majority voting across the rank-310 ing methods, it was possible to find plausible unexplored synergistic combinations that might be prevalent in CRC cells after treatment with ETC-1922159 drug. The two-way cross family analysis also assists in deriving influences between components which serve as hypotheses for further tests. If found true, it paves way for biologists/oncologists to further investigate and understand the mechanism behind the syn-315 ergy through wet experiments. Conflict of interest There are no conflicts to declare. Author’s contributions Concept, design, in silico implementation - SS. Analysis and interpretation of results -320 SS. Manuscript writing - SS. Manuscript revision - SS. 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