Cancer esearch apeutics , Targets , and Chemical Biology thetic Lethality Screens Reveal RPS 6 and MST 1 R as ifiers of Insulin-like Growth Factor-1 Receptor R bitor Activity in Childhood Sarcomas

nloaded insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human s. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking dies show impressive antitumor activity in some but not all patients, and acquired resistance is ed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance s unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhimight be involved. To test this systematically, we performed small interfering RNA (siRNA) screens oma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks odulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that a cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, s ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma es; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; nown as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA rence blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings interfe underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies. Cancer Res; 70(21); 8770–81. ©2010 AACR.