WCLC 2025 - Posters & ePosters-P3.03.12 YAP-Driven Modulation of HER3-Mediated Adaptive Resistance to RET Inhibitors in RET-Altered Cancer

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This study investigates mechanisms underlying adaptive resistance to RET tyrosine kinase inhibitors (RET-TKIs) in RET-altered cancers, particularly lung and thyroid cancers harboring RET fusions or mutations. RET alterations activate RAS/RAF/MEK/ERK pathways promoting tumor survival. Although selpercatinib, a RET-TKI, shows initial efficacy, about 30% of patients develop disease progression within one year, posing a therapeutic challenge.<br /><br />The research identifies that adaptive resistance emerges via reactivation of ERK signaling mediated by HER3 activation following RET-TKI treatment. Transcriptional regulation studies reveal that YAP, a key Hippo pathway effector, is translocated to the nucleus upon RET inhibition, driving HER3 gene expression and thus enabling ERK reactivation and resistance. Cell lines with high YAP expression display reduced sensitivity to RET-TKIs, whereas YAP knockdown suppresses proliferation, suggesting YAP as a potential biomarker for RET-TKI responsiveness.<br /><br />Importantly, combining the pan-HER inhibitor afatinib with selpercatinib effectively suppresses ERK reactivation and cell proliferation in RET-TKI resistant, YAP-high cancer cells in vitro and in vivo. This combination therapy shows superior tumor control compared to single agents. <br /><br />Clinical analysis of 23 RET-positive non-small cell lung cancer patients treated with selpercatinib indicates that low intratumoral cytoplasmic YAP expression correlates with longer progression-free and overall survival, supporting YAP’s role as a predictive biomarker.<br /><br />In conclusion, YAP-driven HER3 activation constitutes a key adaptive resistance mechanism to RET-TKIs. Early combination therapy targeting both RET and HER3 pathways may overcome resistance, and assessing tumor YAP levels can guide treatment stratification for improved outcomes in RET-altered cancers.

Asset Subtitle

Tadaaki Yamada

Meta Tag

Speaker Tadaaki Yamada

Topic Tumor Biology – Translational Biology

Keywords

RET tyrosine kinase inhibitors

adaptive resistance

RET-altered cancers

lung cancer

thyroid cancer

YAP transcription factor

HER3 activation

ERK signaling reactivation

selpercatinib

combination therapy with afatinib