Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas
| Autor: | Paul Zolkind, Gavin P. Dunn, Ann Marie Egloff, Erica K. Barnell, Ravindra Uppaluri, Obi L. Griffith, Tenny Mudianto, Tusar Giri, Rachel S. Riley, Malachi Griffith, Jason Webb, Zachary L. Skidmore, Douglas Adkins, Katie M. Campbell, Ibrahim Ozgenc |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research MAP Kinase Signaling System Pyridones Biopsy Cell Pyrimidinones Article Gene Knockout Techniques Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Exome Sequencing Animals Humans Medicine Hippo Signaling Pathway RNA-Seq Trametinib YAP1 Hippo signaling pathway Squamous Cell Carcinoma of Head and Neck business.industry YAP-Signaling Proteins medicine.disease Xenograft Model Antitumor Assays Head and neck squamous-cell carcinoma Verteporfin Gene Expression Regulation Neoplastic Clinical trial 030104 developmental biology medicine.anatomical_structure Oncology Drug Resistance Neoplasm Head and Neck Neoplasms Cell culture 030220 oncology & carcinogenesis Cancer research Female business medicine.drug |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-19-4179 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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