Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.

Journal: 
Nat Med
Publication Year: 
2014
Authors: 
Christine M Lovly
Nerina T McDonald
Heidi Chen
Sandra Ortiz-Cuaran
Lukas C Heukamp
Yingjun Yan
Alexandra Florin
Luka Ozretic
Diana Lim
Lu Wang
Zhao Chen
Xi Chen
Pengcheng Lu
Paul K Paik
Ronglai Shen
Hailing Jin
Reinhard Buettner
Sascha Ansen
Sven Perner
Michael Brockmann
Marc Bos
Jurgen Wolf
Masyar Gardizi
Gavin M Wright
Benjamin Solomon
Prudence A Russell
Toni-Maree Rogers
Yoshiyuki Suehara
Monica Red-Brewer
Rudy Tieu
Elisa de Stanchina
Qingguo Wang
Zhongming Zhao
David H Johnson
Leora Horn
Kwok-Kin Wong
Roman K Thomas
Marc Ladanyi
William Pao
PubMed link: 
25173427
Public Summary: 
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.
Scientific Abstract: 
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.