IGF1R Signaling Is a Therapeutic Target in ALK Fusion–Positive Lung Cancer

Patients with lung cancer harboring fusions in the anaplastic lymphoma receptor tyrosine kinase (ALK) gene exhibit prolonged progression-free survival following treatment with the ALK tyrosine kinase inhibitor (TKI) crizotinib, but inevitably develop resistance. However, the mechanisms of resistance to ALK inhibition are not fully understood. Lovly and colleagues describe a patient with ALK fusion–positive (ALK⁺) lung cancer who had an exceptional response to insulin-like growth factor 1 receptor (IGF1R) inhibition, suggesting potential crosstalk between IGF1R and ALK. Treatment of ALK⁺ TKI-sensitive lung cancer cell lines with the combination of crizotinib and IGF1R inhibitors resulted in a synergistic decrease in cell proliferation, enhanced apoptosis, and reduced phosphorylation of downstream effectors compared with crizotinib alone. Conversely, the addition of IGF1 promoted crizotinib resistance by inducing IGF1R phosphorylation, indicating that IGF1R signaling may compensate for reduced ALK signaling during crizotinib therapy. Insulin receptor substrate 1 (IRS1), an adaptor protein for IGF1R, also interacted with and functioned as an adaptor protein for ALK, and IRS1 depletion increased the sensitivity of ALK⁺ cells to crizotinib. In addition, ALK TKI–resistant lung cancer cells displayed enhanced IGF1R activation compared with isogenic ALK TKI–sensitive cells, and patient tumor samples showed increased IGF1R and IRS1 levels at the time of crizotinib resistance, validating the relationship between IGF1R and ALK in vivo. Inhibition of IGF1R or knockdown of IRS1 partially restored the sensitivity of ALK TKI–resistant cells to ALK inhibition. Furthermore, LDK-378 (ceritinib), a second-generation ALK inhibitor that has shown activity in patients who progressed on crizotinib, more potently inhibited ALK⁺ xenograft growth than crizotinib and also inhibited IGF1-induced phosphorylation of IGF1R in vitro, suggesting that this agent may function by blocking both ALK and IGF1R. These results identify cooperative effects of ALK and IGF1R inhibitors in ALK⁺ lung cancer and suggest that this combination treatment may limit or overcome resistance to ALK inhibitor therapy.

Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer. Nat Med 2014;20:1027–34.

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