The Molecular Pathogenesis of EML4-ALK Driven Lung Cancer and Strategies to Overcome Clinical Resistance to ALK Inhibitors

A promising strategy to combat cancer drug resistance is to deploy rational upfront polytherapy that suppresses the survival and emergence of resistant tumor cells. The optimal initial combination strategy is unclear in most tumors with oncogenic receptor kinases because they typically engage multiple effector pathways, and which of these individual pathways (if any) is most critical to tumor cell survival is poorly defined. Here, I demonstrate in models of lung adenocarcinoma harboring the oncogenic ALK receptor kinase fusion (EML4-ALK) that the RAS-MAPK pathway, but not other known ALK effectors, is required for tumor cell survival. We reveal that EML4-ALK drives RAS-MAPK activation by engaging all three major RAS isoforms (H, N-, K-RAS), a signaling event that requires the HELP domain of EML4. MAPK pathway reactivation via either genomic amplification of KRASWT or downregulation of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibition. Accordingly, upfront ALK and MEK co-inhibition enhanced both the magnitude and duration of initial response in EML4-ALK lung adenocarcinoma in vitro and in vivo models. Furthermore, genomic amplification (or gene duplication) of KRASWT or downregulation of DUSP6 was observed in ALK fusion positive lung adenocarcinoma patients with acquired ALK inhibitor resistance. Together, my findings provide insight into the function of RAS-MAPK signaling in EML4-ALK lung adenocarcinoma and rationale for upfront ALK-MEK co-inhibition to forestall resistance and improve patient outcomes