SHP2 Inhibition May Resensitize NSCLC Tumors to ALK Inhibitors

In patients with ALK-rearranged non–small cell lung cancer (NSCLC), acquired resistance to ALK inhibitors can occur via multiple mechanisms. Mutations or amplifications affecting ALK can cause resistance to first-generation ALK inhibitors (including crizotinib) and second-generation ALK inhibitors (including ceritinib) and can be overcome by lorlatinib, a selective third-generation ALK inhibitor. The selective activation of alternate kinases, such as EGFR, KIT, SRC, or IGF1R, can also induce resistance to first- and second-generation ALK inhibitors by activating downstream ERK and/or PI3K–AKT signaling, but these resistance mechanisms cannot be overcome by lorlatinib. Dardaei and colleagues performed a pooled shRNA dropout screen on a panel of ALK-rearranged NSCLC cell lines generated from patients who developed resistance to crizotinib or ceritinib to identify treatment approaches that could block acquired resistance in cases without secondary mutations in ALK. This screen identified multiple resistance drivers including the kinases EGFR, ERBB2, SRC, MAPK1, and RAF1 and the phosphatases SHP2 (encoded by PTPN11) and FRS2. SHP2 promotes RAS activation downstream of multiple tyrosine kinases including EGFR, FGFR, and SRC, and depleting SHP2 resensitized patient-derived NSCLC cells to ceritinib and reduced GTP-RAS levels. Further, treatment with the SHP2 inhibitor SHP099 had little effect as a single agent, but in combination with ceritinib, SHP099 reduced proliferation in ceritinib-resistant cells. SHP2 inhibition blocked ERK1/2 reactivation following ceritinib treatment, with cotreatment with SHP099 and ceritinib resulting in durable suppression of ERK1/2 phosphorylation, suggesting the potential for SHP2 inhibition to overcome resistance to tyrosine kinase–mediated bypass signaling. In vivo, combined treatment with ceritinib and SHP009 resulted in a greater suppression of tumor growth than either single-agent therapy, and SHP009 exhibited only minor toxicity. Collectively, these findings suggest that inhibition of SHP2 may suppress ALK inhibitor resistance driven by tyrosine kinase reactivation to potentially improve therapeutic outcomes in patients with ALK-rearranged NSCLC.

Dardaei L, Wang HQ, Singh M, Fordjour P, Shaw KX, Yoda S, et al. SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med 2018 Mar 5 [Epub ahead of print].

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