YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers
Yuki Katayama1, Tadaaki Yamada1, Keiko Tanimura1
1Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Purpose:
Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells.
Experimental Design:
Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion-positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes.
Results:
In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.
Conclusions:
The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment. See related commentary by Ortiz-Cuaran and Leonce, p. 958.
Insights
High YAP expression drives resistance to RET tyrosine kinase inhibitors (TKIs) in RET-aberrant cancers by activating YAP-HER3 signaling. Combining YAP/HER3 inhibition with RET-TKIs offers a potent initial treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Rearranged during transfection (RET) aberrations are targetable oncogenes in various cancers, with RET inhibitors showing efficacy.
- However, resistance to RET tyrosine kinase inhibitors (TKIs) is a significant clinical challenge.
- Mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancers remain largely unknown.
Purpose of the Study:
- To investigate the role of YAP-mediated HER3 signaling in adaptive resistance to RET-TKIs.
- To elucidate the molecular mechanisms underlying drug-tolerant cell emergence in RET-aberrant cancer cells treated with RET-TKIs.
Main Methods:
- Utilized four RET-aberrant cancer cell lines to assess sensitivity to selpercatinib and pralsetinib.
- Employed RNA sequencing, phospho-receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation, and luciferase reporter assays.
- Analyzed clinical specimens from RET fusion-positive lung cancer patients for YAP expression and treatment outcomes.
Main Results:
- High YAP-expressing RET-aberrant cells showed YAP-mediated HER3 activation, promoting survival and tolerance to RET-TKIs.
- Pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors (verteporfin, K-975) sensitized these cells to RET-TKIs.
- Pretreatment YAP expression in lung cancer patients correlated with poor outcomes from RET-TKI therapy.
Conclusions:
- The YAP-HER3 axis is critical for survival and adaptive resistance in high YAP-expressing RET-aberrant cancer cells.
- Combined inhibition of YAP/HER3 with RET-TKIs presents a promising initial therapeutic strategy.
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