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

RAS-MAPK signaling influences the efficacy of ALK-targeting agents in lung cancer

ALK (anaplastic lymphoma kinase) inhibitors are approved in for ALK gene rearrangement positive (ALK+) lung cancer, but resistance remains a challenge. We discovered that RAS-RAF-MEK-ERK signaling controls the ALK inhibitor response in ALK+ lung cancer and is critical for ALK inhibitor resistance. Upfront ALK-MEK inhibitor polytherapy may enhance response and forestall resistance

RAS signaling in ALK fusion lung cancer

The success of ALK targeted therapy is blunted by resistance. To identify rational polytherapy strategies to improve clinical outcomes, we studied the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that RAS-RAF-MEK-ERK signaling is the crucial downstream pathway that is required for ALK+ tumor cell survival. Upfront co-inhibition of ALK and MEK improved response and blocked resistance in preclinical ALK+ lung cancer models, providing rationale for a new treatment paradigm for ALK+ patients

RAS-MAPK signaling influences the efficacy of ALK-targeting agents in lung cancer

ALK (anaplastic lymphoma kinase) inhibitors are approved in for ALK gene rearrangement positive (ALK+) lung cancer, but resistance remains a challenge. We discovered that RAS-RAF-MEK-ERK signaling controls the ALK inhibitor response in ALK+ lung cancer and is critical for ALK inhibitor resistance. Upfront ALK-MEK inhibitor polytherapy may enhance response and forestall resistance

RAS-MAPK in ALK targeted therapy resistance

The clinical success of ALK targeted therapy is limited by resistance. To identify rational co-targeting strategies to enhance clinical outcomes, we explored the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that the RAS-RAF-MEK-ERK pathway is the critical downstream pathway necessary for ALK+ tumor cell survival. Upfront co-targeting of ALK plus MEK enhanced response and forestalled resistance in preclinical ALK+ tumor models, providing rationale for a new approach the treatment of ALK+ patients

RAS-MAPK in ALK targeted therapy resistance

The clinical success of ALK targeted therapy is limited by resistance. To identify rational co-targeting strategies to enhance clinical outcomes, we explored the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that the RAS-RAF-MEK-ERK pathway is the critical downstream pathway necessary for ALK+ tumor cell survival. Upfront co-targeting of ALK plus MEK enhanced response and forestalled resistance in preclinical ALK+ tumor models, providing rationale for a new approach the treatment of ALK+ patients

Mechanisms of resistance to EGFR targeted therapies

EGFR is a validated therapeutic target in many human cancers. EGFR targeted therapies are in widespread clinical use in patients with non-small cell lung cancer and other tumor types. Despite the clinical success of EGFR targeted therapy, resistance to treatment is a significant barrier to the optimized use of EGFR inhibitors to cure patients with lung and other cancers. Here, we review established and emerging mechanisms of resistance to EGFR targeted therapy and highlight strategies that could overcome treatment resistance and therefore enhance clinical outcomes