Abstract
EPHA2 depletion or small molecule inhibition promotes apoptosis in preclinical models of NSCLC.
Major finding: EPHA2 depletion or small molecule inhibition promotes apoptosis in preclinical models of NSCLC.
Mechanism: Activated EPHA2 enhances phosphorylation and prosurvival signaling of p90-RSK and S6 kinase.
Impact: EPHA2 inhibitors may hold promise for the treatment of NSCLC, including tumors with KRAS mutations.
EPH receptor A2 (EPHA2), a receptor tyrosine kinase activated by EPHRIN ligand engagement, is commonly overexpressed in a number of cancers, including non–small cell lung cancer (NSCLC), in which EPHA2 overexpression is associated with relapse and poor patient survival. In preclinical models of breast cancer, EPHA2 expression leads to increased tumor formation, progression, angiogenesis, and therapeutic resistance, but the role of EPHA2 in lung cancer progression is unclear. Amato and colleagues found that genetic deletion of EphA2 in a KrasG12D-driven mouse model of spontaneous, aggressive NSCLC resulted in reduced tumor burden and increased apoptosis. Furthermore, EPHA2 knockdown in a subset of genetically diverse human NSCLC cell lines, including those with KRAS mutations, reduced cell viability, with the most sensitive cell lines displaying higher levels of phosphorylated EPHA2 receptor after EPHRIN-A1 or serum stimulation. In NSCLC subcutaneous xenografts, EPHA2 depletion also reduced tumor volume and increased apoptosis but had no significant effect on proliferation or angiogenesis. In several human NSCLC cell lines, active EPHA2 was required for phosphorylation of p90-RSK, S6 kinase, and BAD, resulting in prosurvival signaling. Treatment with ALW-II-41-27, a selective small molecule ATP-competitive inhibitor of EPHA2, recapitulated molecular and phenotypic consequences of EPHA2 knockdown in vitro. ALW-II-41-27 had poor pharmacokinetic properties in vivo, but frequent high doses of ALW-II-41-27 induced NSCLC xenograft tumor regression with some toxicity, further implicating EPHA2 as a therapeutic target in NSCLC but indicating a need for further development of EPHA2 inhibitors with better bioavailability and tolerability. These results describe a critical role for EPHA2 in the progression of NSCLC through the maintenance of prosurvival signaling pathways and highlight the potential efficacy of targeting EPHA2 in NSCLC, including tumors with KRAS mutations, for which no effective targeted therapy currently exists.
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