7573 Background: Mechanisms of acquired resistance to erlotinib (E) in NSCLC include aberrant activation of alternative receptor tyrosine kinases and/or their downstream signal transduction cascades (e.g, c-Met and AKT), indicating a need for strategies to detect such resistance mechanisms and agents to overcome them. The effects of MK2206, a selective AKT inhibitor, on E activity in NSCLC cell lines with diverse oncogenic mutation profiles and a range of E sensitivity were investigated. We hypothesized that inhibition of AKT signaling would augment E activity and reverse resistance. Methods: Four cell lines were evaluated: HCC827 (EGFR-mutant, E-hypersensitive), H1666 (EGFR-wild type, E-sensitive), H358 (EGFR-wild type, E-sensitive) and A549 (EGFR-wild type, E-resistant). Treatment effects were assessed by MTT assay, colony formation, flow cytometry and immunoblotting for signaling and apoptosis. Results: The combination of MK2206 and E showed significantly enhanced growth inhibition compared to single-agent treatment in all lines tested, including E-resistant cells. Addition of the c-Met ligand, HGF, blocked anti-proliferative and cytotoxic effects of E. Treatment with MK-2206 restored E sensitivity in cells rendered resistant by HGF. In comparison, c-Met inhibition (using PHA665752) effectively overcame HGF-mediated resistance, but was ineffective as a single agent or in combination with E. In E-resistant A549 cells, the addition of MK2206 significantly reduced colony formation compared to the single agents. Conclusions: MK2206 enhanced E activity in both E-sensitive and E-resistant NSCLC cell lines, and re-sensitized cells rendered resistant through c-Met activation by HGF. This paradigm is currently being tested in an ongoing NCI-sponsored phase II trial of MK-2206 in combination with E in patients with advanced NSCLC (stratified by EGFR mutational status) who have previously benefited from E-based therapy.
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Mack et al. (2011) studied this question.