Evolution of Targeted Therapy Resistance in EML4-ALK Positive Non-Small Cell Lung Cancer

Targeted therapies have emerged as potent treatments that lead to the remission of many tumors. However, they rarely cure cancers in advanced, metastatic settings. This is due to the evolution of resistance, which in turn can be ascribed to the survival of small subpopulations of tolerant and/or resistant cells. Here we investigated the evolution of resistance to EML4-ALK inhibitors in non-small cell lung cancer (NSCLC) and demonstrated that resistance evolves gradually, from unique pre-treatment sub-populations, as multiple resistance mechanisms accumulate in a Darwinian fashion. Despite accumulating multiple changes, cells evolved, in parallel, toward similar inhibitor specific phenotypes. Evolving cells have unique vulnerabilities that can be targeted with collateral sensitivity agents before full resistance evolves. These conclusions, obtained from in vitro studies, are applicable to the evolution of resistance in vivo. However, the evolution of resistance in vivo is also strongly influenced by microenvironmental therapy resistance. These findings could allow physicians to base treatment strategies on the future evolutionary trajectories of tumors and exploit unique vulnerabilities not just after, but during, the evolution of resistance