IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma

摘要: The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles pro-survival and anti-apoptotic signaling. However, development of resistance IGF-1R blockade represents hindrance limits treatment efficacy the clinic. In this study, we identified acquired with R1507, an antibody against IGF-1R, BMS-754807, small molecular inhibitor IGF-1R/insulin (IR). We showed that IGF-IR antibody, or IR/IGF-IR kinase inhibitor, was associated increased activation YES/SRC family tyrosine (SFK) rhabdomyosarcoma (RMS). Combining anti–IGF-1R agents SFK inhibitors resulted inhibition–induced YES/SFK displayed advantageous antitumor activity vitro vivo. Our data provide evidence results bypass pathway This may be particular clinical relevance since both Yes IGF components are overexpressed RMS. Increased might serve biomarker for predicting tumor inhibition. Dual inhibition have broader enhanced benefit patients