Abstract 2688: Inhibition of CDK7 using small molecule inhibitor, TGN-1062, augments the effect of cisplatin treatment in head and neck PDX models

Purpose: Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most prevalent type of cancer in the world with incidence rates projected to increase 30% by 2030. This increase is generally associated with cultural and environmental risk factors such as tobacco consumption, alcohol abuse, airborne pollutants, and exposure to human papilloma virus. Standard of care (SOC) therapy remains multimodal relying primarily on surgical resections followed by chemotherapy and radiation. Screening methods have proven to be ineffective and improvements to treatment over the past decade have only been modest. While there are some successful treatments, like use of cetuximab in patients with EGFR expressing tumors, there is still a major unmet need in this area. Overexpression of Cyclin-Dependent Kinase 7 (CDK7) is highly associated with poor prognosis in HNSCC. CDK7 plays a dual role in tumor progression by regulating the cell cycle via phosphorylation of members of the CDK family and stimulation of transcription via phosphorylation of RNA Polymerase II. CDK7 has also been shown to be associated with super-enhancers which can lead to overexpression of oncogenic driver genes such as BCL2, GFI1, MYC, and pMED1. Previously, we have presented the development of a potent and reversible CDK7 inhibitor, TGN-1062. Here, we have generated data suggesting the potential benefit of CDK7 inhibition in combination with SOC therapy for HNSCC. Methods: HNSCC lines were co-treated with cisplatin and TGN-1062, assessed for viabilities with CellTiter-Glo, and analyzed with the Bliss synergy model. In vivo efficacy studies were conducted at Crown Bioscience. HNSCC PDX tumors were implanted and treated with TGN-1062 with and without Cisplatin. Tumors were measured to determine tumor growth inhibition (TGI) and correlating drug accumulation levels were measured in both tumors and plasma using mass spectrometry. Immunohistochemistry (IHC) and RT-PCR were performed on tumors to determine changes in cleaved Caspase- 3, MYC, and RNA Pol II. Results: TGN-1062 induces a dose dependent change in biomarkers shown via Western blotting. Synergistic effects are observed at certain ratios of TGN-1062 and Cisplatin on HNSCC cells. Co-treatment with cisplatin and TGN-1062 in HN2579 PDX showed the most combination benefit with 64% TGI, an improvement over cisplatin treatment alone at 54% TGI. Improvement to cisplatin treatment was also observed in the HN3540 PDX at end of study with cisplatin and TGN-106