RT Journal Article
SR Electronic
T1 Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 504837
DO 10.1101/504837
A1 Robert Vander Velde
A1 Nara Yoon
A1 Viktoriya Marusyk
A1 Arda Durmaz
A1 Andrew Dhawan
A1 Daria Myroshnychenko
A1 Diego Lozano-Peral
A1 Bina Desai
A1 Olena Balynska
A1 Jan Poleszhuk
A1 Liu Kenian
A1 Mohamed Abazeed
A1 Omar Mian
A1 Aik Choon Tan
A1 Eric Haura
A1 Jacob Scott
A1 Andriy Marusyk
YR 2019
UL http://biorxiv.org/content/early/2019/11/19/504837.abstract
AB Despite high initial efficacy, therapies that target oncogenic kinases eventually fail in advanced, metastatic cancers. This failure in initially responsive tumors is the direct result of the evolution of drug resistance under therapy-imposed selective pressures. In contrast to the massive body of experimental research on the molecular mechanisms of resistance, understanding of its evolutionary origins and dynamics remains fragmented. Using a combination of experimental studies and mathematical modeling, we sought to dissect the evolution of resistance to different clinical ALK inhibitors in an experimental model of ALK positive NSCLC. We found that resistance can originate from heterogeneous, weakly resistant, sub-populations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence of a hybrid scenario, of gradual, multifactorial development through acquisition of multiple cooperating genetic and epigenetic adaptive changes, amplified by selection. Additionally, we found that intermediate resistance phenotypes might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting new opportunities for therapeutic interference.