Downregulation of PDGFR? Signaling Overcomes Crizotinib Resistance in a TYRO3 and ALK Mutated Neuroendocrine-Like Tumor

摘要

Patient-derived xenografts provide significant advantages over long-term passage cell lines when investigating efficacy of treatments for solid tumors. Our laboratory encountered a high-grade, metastatic, neuroendocrine-like tumor from a pediatric patient that presented with a unique genetic profile. In particular, mutations inTYRO3andALKwere identified. We established a human patient-derived xenoline (PDX) of this tumor for use in the current study. We investigated the effect of crizotinib, a chemotherapeutic known to effectively target bothTYRO3andALKmutations. Crizotinib effectively decreased viability, proliferation, growth, and the metastatic properties of the PDX tumor through downregulation of STAT3 signaling, but expression of PDGFR? was increased. Sunitinib is a small molecule inhibitor of PDGFR? and was studied in this PDX independently and in combination with crizotinib. Sunitinib alone decreased viability, proliferation, and growthin vitroand decreased tumor growthin vivo. In combination, sunitinib was able to overcome potential crizotinib-induced resistance through downregulation of ERK 1/2 activity and PDGFR? receptor expression; consequently, tumor growth was significantly decreased bothin vitroandin vivo.Through the use of the PDX, it was possible to identify crizotinib as a less effective therapeutic for this tumor and suggest that targeting PDGFR? would be more effective. These findings may translate to other solid tumors that present with the same genetic mutations.