RNA-seq of RET-aberrant cancer cell lines treated with RET-TKI selpercatinib

RET-aberrant cancer discovered as a relevant targetable oncogene in several types of tumors, whose inhibitors have marked efficacy. However, some of patients with RET-aberrant cancer are insensitive to RET- tyrosine kinase inhibitors (TKIs) and are clinically non-responders. Recently, drug-tolerant mechanisms have been gaining attention as targets for initial therapies aimed at overcoming drug resistance. However, the underlying mechanisms of drug-tolerant cells emergence treated with RET-TKIs derived from RET-aberrant cancer cells remains unknown. In this study, HER3 signal activity through YAP1 was led to maintaining cell survival and inducing the emergence of cells tolerant to RET-TKIs selpercatinib and pralsetinib in high YAP1 expressed RET- rearranged cancer cells. These results suggested that YAP1-HER3 axis plays pivotal roles for cell survival under an exposure with RET-TKIs in the intrinsic resistance to RET-TKIs and the emergence of tolerant cells by RET-TKIs in YAP1 expressed RET-aberrant cancer, suggesting that YAP1/HER3 inhibition and RET-TKIs is a highly potent combination for initial treatment.