Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures.

ABSTRACT: Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations 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 for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of mult

SUBMITTER: Vander Velde R 

PROVIDER: S-EPMC7224215 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature