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Ref Type Journal Article
PMID (25173427)
Authors Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, Florin A, Ozretic L, Lim D, Wang L, Chen Z, Chen X, Lu P, Paik PK, Shen R, Jin H, Buettner R, Ansen S, Perner S, Brockmann M, Bos M, Wolf J, Gardizi M, Wright GM, Solomon B, Russell PA, Rogers TM, Suehara Y, Red-Brewer M, Tieu R, de Stanchina E, Wang Q, Zhao Z, Johnson DH, Horn L, Wong KK, Thomas RK, Ladanyi M, Pao W
Title Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Journal Vol Issue Date Pages Journal Short Title
Nature medicine 20 9 2014 Sep 1027-34 Nat Med
URL
Abstract Text Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK lung non-small cell carcinoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited phosphorylation of Alk and inhibited growth of human non-small cell lung cancer cell lines harboring EML4-ALK in culture (PMID: 25173427). 25173427