☆ 4.7 Article

Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas

CLINICAL CANCER RESEARCH (2021)

Journal

CLINICAL CANCER RESEARCH

Volume 27, Issue 8, Pages 2326-2339

Publisher

AMER ASSOC CANCER RESEARCH

DOI: 10.1158/1078-0432.CCR-19-4179

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Funding

NIH/NIDCR [DE024403, DE027736]
V Foundation Translational Research Award
National Comprehensive Cancer Network (NCCN) Oncology Research Program from Novartis Pharmaceutical Corporation (Novartis)
NCI [NIH NCI K22CA188163, NIH NCI U01CA209936, NIH NCI U24CA237719]
Cancer Research Foundation Young Investigator Award

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Abstract

The study revealed a Yap1-dependent resistance to trametinib therapy in HNSCCs, with downstream effectors of the Hippo pathway being activated. Combined targeting of Yap1 and MEK may enhance the therapeutic response in head and neck squamous cell carcinoma. The findings suggest potential strategies to overcome resistance and improve treatment outcomes.

Purpose: In a head and neck squamous cell carcinoma (HNSCC) window of opportunity clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples. Experimental Design: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing. Results: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity. Conclusions: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.

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YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4

Nana Chen, Gabriel Golczer, Subhoshree Ghose, Brian Lin, Adam Langenbucher, Jason Webb, Haymanti Bhanot, Nicholas B. Abt, Derrick Lin, Mark Varvares, Martin Sattler, Ann Marie Egloff, Richard Joh, Ravindra Uppaluri, Kevin S. Emerick, Michael S. Lawrence, Srinivas Vinod Saladi

Summary: Analysis of HNSCC data reveals frequent mutations in the FAT1 gene, which are associated with increased sensitivity to BRD4 inhibition by JQ1. This study uncovers the cooperative mechanism between YAP1 and BRD4 in HNSCC and suggests a specific therapeutic opportunity for a subset of head and neck cancer patients.

CELL REPORTS (2022)