Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Opinion Article

Experimental Determination of Cancer Drug Targets with Independent Mechanisms of Resistance

Author(s): Abigail R. Bland, Nensi Shrestha, Maddie Berry, Christabel Wilson and John C. Ashton*

Volume 22, Issue 2, 2022

Published on: 08 March, 2022

Page: [97 - 107] Pages: 11

DOI: 10.2174/1568009622666220107152014

Price: $65

Abstract

Mathematical modelling of tumour mutation dynamics has suggested that cancer drug targets that have different resistance mechanisms should be good candidates for combination treatment. This is because the development of mutations that cause resistance to all drugs at once should arise relatively infrequently. However, it is difficult to identify drug targets fulfilling this requirement for particular cancers. Here we present four experimental criteria that we argue are necessary (but not sufficient) conditions that drug combinations should meet in order to be considered for combination drug treatment aimed at delaying or overcoming cancer drug resistance. We present the results of our own experiments - guided by these criteria - using anaplastic lymphoma kinase mutated lung cancer cells. Each set of experiments demonstrate results for different drug combinations. We conclude that the combination of ALK and MEK inhibitors come closest to meeting all our criteria.

Keywords: ALK, drug resistance, combination treatment, lung cancer, mathematical modelling, drug targets.

« Previous Next »
Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[2]
Wilcox, W.S. The last surviving cancer cell: The chances of killing it. Cancer Chemother. Rep., 1966, 50(8), 541-542.
[PMID: 5978726]
[3]
Perelson, A.S.; Neumann, A.U.; Markowitz, M.; Leonard, J.M.; Ho, D.D. HIV-1 dynamics in vivo: Virion clearance rate, infected cell life-span, and viral generation time. Science, 1996, 271(5255), 1582-1586.
[http://dx.doi.org/10.1126/science.271.5255.1582] [PMID: 8599114]
[4]
Altrock, P.M.; Liu, L.L.; Michor, F. The mathematics of cancer: Integrating quantitative models. Nat. Rev. Cancer, 2015, 15(12), 730-745.
[http://dx.doi.org/10.1038/nrc4029] [PMID: 26597528]
[5]
Chisholm, R.H.; Lorenzi, T.; Clairambault, J. Cell population heterogeneity and evolution towards drug resistance in cancer: Biological and mathematical assessment, theoretical treatment optimisation. Biochim. Biophys. Acta, 2016, 1860(11 Pt B), 2627-2645.
[http://dx.doi.org/10.1016/j.bbagen.2016.06.009] [PMID: 27339473]
[6]
Bozic, I.; Nowak, M.A. Resisting resistance. Ann. Rev. Cancer Biol., 2017, 1, 203-221.
[http://dx.doi.org/10.1146/annurev-cancerbio-042716-094839]
[7]
Bozic, I.; Reiter, J.G.; Allen, B.; Antal, T.; Chatterjee, K.; Shah, P.; Moon, Y.S.; Yaqubie, A.; Kelly, N.; Le, D.T.; Lipson, E.J.; Chapman, P.B.; Diaz, L.A., Jr; Vogelstein, B.; Nowak, M.A. Evolutionary dynamics of cancer in response to targeted combination therapy. elife, 2013, 2, e00747.
[8]
Sun, X.; Hu, B. Mathematical modeling and computational prediction of cancer drug resistance. Brief. Bioinform., 2018, 19(6), 1382-1399.
[http://dx.doi.org/10.1093/bib/bbx065] [PMID: 28981626]
[9]
Camidge, D.R.; Kono, S.A.; Lu, X.; Okuyama, S.; Barón, A.E.; Oton, A.B.; Davies, A.M.; Varella-Garcia, M.; Franklin, W.; Doebele, R.C. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J. Thorac. Oncol., 2011, 6(4), 774-780.
[http://dx.doi.org/10.1097/JTO.0b013e31820cf053] [PMID: 21336183]
[10]
Shaw, A.T.; Varghese, A.M.; Solomon, B.J.; Costa, D.B.; Novello, S.; Mino-Kenudson, M.; Awad, M.M.; Engelman, J.A.; Riely, G.J.; Monica, V.; Yeap, B.Y.; Scagliotti, G.V. Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer. Ann. Oncol., 2013, 24(1), 59-66.
[http://dx.doi.org/10.1093/annonc/mds242] [PMID: 22887466]
[11]
Berge, E.M.; Lu, X.; Maxson, D.; Barón, A.E.; Gadgeel, S.M.; Solomon, B.J.; Doebele, R.C.; Varella-Garcia, M.; Camidge, D.R. Clinical benefit from pemetrexed before and after crizotinib exposure and from crizotinib before and after pemetrexed exposure in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. Clin. Lung Cancer, 2013, 14(6), 636-643.
[http://dx.doi.org/10.1016/j.cllc.2013.06.005] [PMID: 23931899]
[12]
Shaw, A.T.; Friboulet, L.; Leshchiner, I.; Gainor, J.F.; Bergqvist, S.; Brooun, A.; Burke, B.J.; Deng, Y.L.; Liu, W.; Dardaei, L.; Frias, R.L.; Schultz, K.R.; Logan, J.; James, L.P.; Smeal, T.; Timofeevski, S.; Katayama, R.; Iafrate, A.J.; Le, L.; McTigue, M.; Getz, G.; Johnson, T.W.; Engelman, J.A. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N. Engl. J. Med., 2016, 374(1), 54-61.
[http://dx.doi.org/10.1056/NEJMoa1508887] [PMID: 26698910]
[13]
Bland, A.R.; Bower, R.L.; Nimick, M.; Hawkins, B.C.; Rosengren, R.J.; Ashton, J.C. Cytotoxicity of curcumin derivatives in ALK positive non-small cell lung cancer. Eur. J. Pharmacol., 2019, 865, 172749.
[http://dx.doi.org/10.1016/j.ejphar.2019.172749] [PMID: 31654622]
[14]
Kashif, M.; Andersson, C.; Mansoori, S.; Larsson, R.; Nygren, P.; Gustafsson, M.G. Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism. Oncotarget, 2017, 8(61), 103952-103967.
[http://dx.doi.org/10.18632/oncotarget.21895] [PMID: 29262612]
[15]
Goutelle, S.; Maurin, M.; Rougier, F.; Barbaut, X.; Bourguignon, L.; Ducher, M.; Maire, P. The Hill equation: A review of its capabilities in pharmacological modelling. Fundam. Clin. Pharmacol., 2008, 22(6), 633-648.
[http://dx.doi.org/10.1111/j.1472-8206.2008.00633.x] [PMID: 19049668]
[16]
Sosman, J.A.; Kim, K.B.; Schuchter, L.; Gonzalez, R.; Pavlick, A.C.; Weber, J.S.; McArthur, G.A.; Hutson, T.E.; Moschos, S.J.; Flaherty, K.T.; Hersey, P.; Kefford, R.; Lawrence, D.; Puzanov, I.; Lewis, K.D.; Amaravadi, R.K.; Chmielowski, B.; Lawrence, H.J.; Shyr, Y.; Ye, F.; Li, J.; Nolop, K.B.; Lee, R.J.; Joe, A.K.; Ribas, A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med., 2012, 366(8), 707-714.
[http://dx.doi.org/10.1056/NEJMoa1112302] [PMID: 22356324]
[17]
Vogel, C.L.; Cobleigh, M.A.; Tripathy, D.; Gutheil, J.C.; Harris, L.N.; Fehrenbacher, L.; Slamon, D.J.; Murphy, M.; Novotny, W.F.; Burchmore, M.; Shak, S.; Stewart, S.J.; Press, M. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol., 2002, 20(3), 719-726.
[http://dx.doi.org/10.1200/JCO.2002.20.3.719] [PMID: 11821453]
[18]
Wilson, C.; Nimick, M.; Nehoff, H.; Ashton, J.C. ALK and IGF-1R as independent targets in crizotinib resistant lung cancer. Sci. Rep., 2017, 7(1), 13955.
[http://dx.doi.org/10.1038/s41598-017-14289-w] [PMID: 29066738]
[19]
Morris, S.W.; Kirstein, M.N.; Valentine, M.B.; Dittmer, K.G.; Shapiro, D.N.; Saltman, D.L.; Look, A.T. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science, 1994, 263(5151), 1281-1284.
[http://dx.doi.org/10.1126/science.8122112] [PMID: 8122112]
[20]
Soda, M.; Choi, Y.L.; Enomoto, M.; Takada, S.; Yamashita, Y.; Ishikawa, S.; Fujiwara, S.; Watanabe, H.; Kurashina, K.; Hatanaka, H.; Bando, M.; Ohno, S.; Ishikawa, Y.; Aburatani, H.; Niki, T.; Sohara, Y.; Sugiyama, Y.; Mano, H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007, 448(7153), 561-566.
[http://dx.doi.org/10.1038/nature05945] [PMID: 17625570]
[21]
Pacheco, J.M.; Gao, D.; Smith, D.; Purcell, T.; Hancock, M.; Bunn, P.; Robin, T.; Liu, A.; Karam, S.; Gaspar, L.; Kavanagh, B.; Rusthoven, C.; Aisner, D.; Doebele, R.; Camidge, D.R. Natural history and factors associated with overall survival in stage IV ALK-rearranged non-small cell lung cancer. J. Thorac. Oncol., 2019, 14(4), 691-700.
[http://dx.doi.org/10.1016/j.jtho.2018.12.014] [PMID: 30599201]
[22]
Witek, B.; El Wakil, A.; Nord, C.; Ahlgren, U.; Eriksson, M.; Vernersson-Lindahl, E.; Helland, Å.; Alexeyev, O.A.; Hallberg, B.; Palmer, R.H. Targeted disruption of ALK reveals a potential role in hypogonadotropic hypogonadism. PLoS One, 2015, 10(5), e0123542.
[http://dx.doi.org/10.1371/journal.pone.0123542] [PMID: 25955180]
[23]
Peters, S.; Camidge, D.R.; Shaw, A.T.; Gadgeel, S.; Ahn, J.S.; Kim, D.W.; Ou, S.I.; Pérol, M.; Dziadziuszko, R.; Rosell, R.; Zeaiter, A.; Mitry, E.; Golding, S.; Balas, B.; Noe, J.; Morcos, P.N.; Mok, T. Alectinib versus crizotinib in untreated ALK-positive non small-cell lung cancer. N. Engl. J. Med., 2017, 377(9), 829-838.
[http://dx.doi.org/10.1056/NEJMoa1704795] [PMID: 28586279]
[24]
Chae, Y.K.; Arya, A.; Malecek, M.K.; Shin, D.S.; Carneiro, B.; Chandra, S.; Kaplan, J.; Kalyan, A.; Altman, J.K.; Platanias, L.; Giles, F. Repurposing metformin for cancer treatment: Current clinical studies. Oncotarget, 2016, 7(26), 40767-40780.
[http://dx.doi.org/10.18632/oncotarget.8194] [PMID: 27004404]
[25]
Li, L.; Wang, Y.; Peng, T.; Zhang, K.; Lin, C.; Han, R.; Lu, C.; He, Y. Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway. Oncotarget, 2016, 7(23), 34442-34452.
[http://dx.doi.org/10.18632/oncotarget.9120] [PMID: 27144340]
[26]
Mohammed, A.; Janakiram, N.B.; Brewer, M.; Ritchie, R.L.; Marya, A.; Lightfoot, S.; Steele, V.E.; Rao, C.V. Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl. Oncol., 2013, 6(6), 649-659.
[http://dx.doi.org/10.1593/tlo.13556] [PMID: 24466367]
[27]
Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutlu, G.M.; Budigner, G.S.; Chandel, N.S. Chandel, Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. elife, 2014, 3, e02242.
[28]
Zhuang, Y.; Miskimins, W.K. Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J. Mol. Signal., 2008, 3(1), 18.
[http://dx.doi.org/10.1186/1750-2187-3-18] [PMID: 19046439]
[29]
Jalving, M.; Gietema, J.A.; Lefrandt, J.D.; de Jong, S.; Reyners, A.K.L.; Gans, R.O.B.; de Vries, E.G.E. Metformin: Taking away the candy for cancer? Eur. J. Cancer, 2010, 46(13), 2369-2380.
[http://dx.doi.org/10.1016/j.ejca.2010.06.012] [PMID: 20656475]
[30]
Kourelis, T.V.; Siegel, R.D. Metformin and cancer: New applications for an old drug. Med. Oncol., 2012, 29(2), 1314-1327.
[http://dx.doi.org/10.1007/s12032-011-9846-7] [PMID: 21301998]
[31]
Bland, A.R.; Shrestha, N.; Bower, R.L.; Rosengren, R.J.; Ashton, J.C. The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models. Biochem. Pharmacol., 2021, 183, 114345.
[http://dx.doi.org/10.1016/j.bcp.2020.114345] [PMID: 33227290]
[32]
DaCosta Byfield, S.; Chastek, B.; Korrer, S.; Horstman, T.; Malin, J.; Newcomer, L. Real-world outcomes and value of first-line therapy for metastatic non-small cell lung cancer†. Cancer Invest., 2020, 38(10), 608-617.
[http://dx.doi.org/10.1080/07357907.2020.1827415] [PMID: 33107767]
[33]
Lovly, C.M.; McDonald, N.T.; Chen, H.; Ortiz-Cuaran, S.; Heukamp, L.C.; Yan, Y.; Florin, A.; Ozretić, L.; Lim, D.; Wang, L.; Chen, Z.; Chen, X.; Lu, P.; Paik, P.K.; Shen, R.; Jin, H.; Buettner, R.; Ansén, S.; Perner, S.; Brockmann, M.; Bos, M.; Wolf, J.; Gardizi, M.; Wright, G.M.; Solomon, B.; Russell, P.A.; Rogers, T.M.; Suehara, Y.; Red-Brewer, M.; Tieu, R.; de Stanchina, E.; Wang, Q.; Zhao, Z.; Johnson, D.H.; Horn, L.; Wong, K.K.; Thomas, R.K.; Ladanyi, M.; Pao, W. Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat. Med., 2014, 20(9), 1027-1034.
[http://dx.doi.org/10.1038/nm.3667] [PMID: 25173427]
[34]
Tanizaki, J.; Okamoto, I.; Takezawa, K.; Sakai, K.; Azuma, K.; Kuwata, K.; Yamaguchi, H.; Hatashita, E.; Nishio, K.; Janne, P.A.; Nakagawa, K. Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. Br. J. Cancer, 2012, 106(4), 763-767.
[http://dx.doi.org/10.1038/bjc.2011.586] [PMID: 22240786]
[35]
Hrustanovic, G.; Olivas, V.; Pazarentzos, E.; Tulpule, A.; Asthana, S.; Blakely, C.M.; Okimoto, R.A.; Lin, L.; Neel, D.S.; Sabnis, A.; Flanagan, J.; Chan, E.; Varella-Garcia, M.; Aisner, D.L.; Vaishnavi, A.; Ou, S.H.; Collisson, E.A.; Ichihara, E.; Mack, P.C.; Lovly, C.M.; Karachaliou, N.; Rosell, R.; Riess, J.W.; Doebele, R.C.; Bivona, T.G. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat. Med., 2015, 21(9), 1038-1047.
[http://dx.doi.org/10.1038/nm.3930] [PMID: 26301689]
[36]
Crystal, A.S.; Shaw, A.T.; Sequist, L.V.; Friboulet, L.; Niederst, M.J.; Lockerman, E.L.; Frias, R.L.; Gainor, J.F.; Amzallag, A.; Greninger, P.; Lee, D.; Kalsy, A.; Gomez-Caraballo, M.; Elamine, L.; Howe, E.; Hur, W.; Lifshits, E.; Robinson, H.E.; Katayama, R.; Faber, A.C.; Awad, M.M.; Ramaswamy, S.; Mino-Kenudson, M.; Iafrate, A.J.; Benes, C.H.; Engelman, J.A. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science, 2014, 346(6216), 1480-1486.
[http://dx.doi.org/10.1126/science.1254721] [PMID: 25394791]
[37]
Yoshida, R.; Sasaki, T.; Minami, Y.; Hibino, Y.; Okumura, S.; Sado, M.; Miyokawa, N.; Hayashi, S.; Kitada, M.; Ohsaki, Y. Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer. Int. J. Oncol., 2017, 51(5), 1533-1540.
[http://dx.doi.org/10.3892/ijo.2017.4140] [PMID: 29048652]
[38]
Dagogo-Jack, I. A, Phase IB/II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC. ClinicalTrials.gov, 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT03202940.
[39]
Potter, L.; Blakely, C. Ceritinib + trametinib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). ClinicalTrials.gov, 2020. Avaialble from: https://clinicaltrials.gov/ct2/show/NCT03087448.
[40]
Shrestha, N.; Nimick, M.; Dass, P.; Rosengren, R.J.; Ashton, J.C. Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer. Sci. Rep., 2019, 9(1), 18842.
[http://dx.doi.org/10.1038/s41598-019-55376-4] [PMID: 31827192]

Rights & Permissions Print Cite
Article Metrics
36
1
© 2024 Bentham Science Publishers | Privacy Policy