Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas
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Abstract
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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PDX models recapitulate the biological property and molecular heterogeneity of human cancers and are an ideal preclinical model for inferring clinical performance.
“PDX models that recapitulate the biological property and molecular heterogeneity of human cancers have been considered as an ideal preclinical model for inferring clinical performance (6, 43)”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [43]
The Results section (page unavailable) reports that HNSCC PDXs showed genomic fidelity to their primary tumors and that one PDX’s trametinib response paralleled its patient’s response. It does not establish that PDXs generally retain the molecular heterogeneity of human cancers or are an ideal model for predicting clinical performance. (LLM, conf=0.85)
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YAP1 Is a Crucial Nexus in the Tumor Microenvironment
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Basroparib inhibits YAP ‐driven cancers by stabilizing angiomotin
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- Authors
- Mudianto, T., Campbell, K. M., Webb, J., Zolkind, P., Skidmore, Z. L., Riley, R., Barnell, E. K., Ozgenc, I., Giri, T., Dunn, G. P., Adkins, D. R., Griffith, M., Egloff, A. M., Griffith, O. L., & Uppaluri, R.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Washington University in St. Louis (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Uppaluri, Ravindra
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-02-05
- Volume
- 27
- Issue
- 8
- Pages
- 2326-2339
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC8046740
- OpenAlex
- W3126871726
- Cited by
- 33
- References
- 54
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 8
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NIDCR (DE024403, DE027736)
- NCI NIH (K22CA188163, U01CA209936, U24CA237719)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Keywords
- YAP, trametinib resistance, head and neck squamous cell carcinoma, MEK/ERK1/2 pathway, Hippo signaling pathway, verteporfin, combination therapy, bypass signaling pathways, patient-derived xenografts, neoadjuvant therapy, drug resistance mechanisms
- MeSH terms
- Exome Sequencing, Squamous Cell Carcinoma of Head and Neck, RNA-Seq, Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Biopsy, Female, Head and Neck Neoplasms, Humans, Pyridones, Pyrimidinones, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Gene Knockout Techniques
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