"Role of Amplified Protein Kinases in Head and Neck Squamous Cell Carcinoma Progression and Therapy Resistance."

摘要

ABSTRACT Head and neck squamous cell carcinomas (HNSCC) are the sixth most frequent cancer, but treatments for HNSCC are still limited. Current management of HNSCC often involves surgery and chemo-radiotherapy, the latest alone or combined with cetuximab, an EGFR-targeting monoclonal antibody, or immune checkpoint inhibitors. These regimes usually concur with comorbidities such as jaw stiffness, dysphagia, and swallowing and speech impairments, and HNSCC are often refractory to existing treatments. Chromosome copy number variations (i.e., gain or loss of chromosome regions) are the most common genetic alterations in HNSCC; one of the most prevalent is the `3q amplicon', i.e., the amplification of the distal segment of chromosome 3. To identify alternative targets for intervention in HNSCC, we have scanned for protein kinases within the `3q amplicon'. We recently defined amplified TNIK, a serine/threonine protein kinase encoded within the `3q amplicon', as a promising target in lung squamous cell carcinoma (LSCC). We found that TNIK inhibition suppressed the growth of LSCC patient-derived xenografts. Consistently, in HNSCC cell lines with TNIK amplification, inhibiting TNIK reduced HNSCC cell viability. Mechanistically, TNIK promotes LSCC cell viability by activating the focal adhesion kinase (FAK) and the YAP and TAZ (YAP/TAZ) transcription factors. FAK and YAP/TAZ are frequently aberrantly activated in HNSCC, and these two pathways are known to contribute to HNSCC progression and therapy resistance in multiple tumor types. Given that TNIK is amplified in 20% of HNSCC and its downstream effectors activated, we propose a model in which amplified TNIK is an oncogenic driver that activates essential signaling pathways responsible for controlling cell viability and promoting therapy resistance in HNSCC. To test this model, we propose two Specific Aims. In Aim 1, we will test whether TNIK sustains HNSCC cell proliferation and viability by activating FAK and YAP/TAZ. In Aim 2, we will investigate whether and how inhibiting TNIK sensitizes HNSCC cells to chemotherapy and EGFR-targeting monoclonal antibodies in HNSCC cells. We will test these two aims by using a combination of cell-based proliferation and survival assays, coupled with pharmacological and genetic approaches to target TNIK, FAK, and YAP/TAZ. These studies will identify new mechanisms of HNSCC progression and chemoresistance. This proposal will enable us to generate new hypotheses for a competitive R01 application to study the consequences of targeting TNIK in preclinical models of HNSCC in alignment with our long-term goal of identifying new therapeutic targets for intervention in HNSCC.