Upregulation of IGF1R by mutant RAS in leukemia and potentiation of RAS signaling inhibitors by small-molecule inhibition of IGF1R

Ellen Weisberg, Atsushi Nonami, Zhao Chen, Erik Nelson, Yongfei Chen, Feiyang Liu, Hae Yeon Cho, Jianming Zhang, Martin Sattler, Constantine Mitsiades, Kwok Kin Wong, Qingsong Liu, Nathanael S. Gray, James D. Griffin

研究成果: Contribution to journalArticle査読

11 被引用数 (Scopus)

抄録

Purpose: Activating mutations in the RAS oncogene occur frequently in human leukemias. Direct targeting of RAS has proven to be challenging, although targeting of downstream RAS mediators, such as MEK, is currently being tested clinically. Given the complexity of RAS signaling, it is likely that combinations of targeted agents will be more effective than single agents. Experimental Design: A chemical screen using RAS-dependent leukemia cells was developed to identify compounds with unanticipated activity in the presence of an MEK inhibitor and led to identification of inhibitors of IGF1R. Results were validated using cell-based proliferation, apoptosis, cell-cycle, and gene knockdown assays; immunoprecipitation and immunoblotting; and a noninvasive in vivo bioluminescence model of acute myeloid leukemia (AML). Results: Mechanistically, IGF1R protein expression/activity was substantially increased in mutant RASexpressing cells, and suppression of RAS led to decreases in IGF1R. Synergy between MEK and IGF1R inhibitors correlated with induction of apoptosis, inhibition of cell-cycle progression, and decreased phospho-S6 and phospho-4E-BP1. In vivo, NSG mice tail veins injected with OCI-AML3-luc+ cells showed significantly lower tumor burden following 1 week of daily oral administration of 50 mg/kg NVP-AEW541 (IGF1R inhibitor) combined with 25 mg/kg AZD6244 (MEK inhibitor), as compared with mice treated with either agent alone. Drug combination effects observed in cell-based assays were generalized to additional mutant RAS-positive neoplasms. Conclusions: The finding that downstream inhibitors of RAS signaling and IGF1R inhibitors have synergistic activity warrants further clinical investigation of IGF1R and RAS signaling inhibition as a potential treatment strategy for RAS-driven malignancies.

本文言語英語
ページ(範囲)5483-5495
ページ数13
ジャーナルClinical Cancer Research
20
21
DOI
出版ステータス出版済み - 11 1 2014
外部発表はい

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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