Combining Chk1/2 inhibition with radiation in head and neck cancer

Despite the effectiveness of nonsurgical standard treatments, the survival rates of high risk head and neck cancer patients still remains <50%. Therefore, new targeted therapeutic approaches are needed to improve the outcomes of patients with advanced high risk head and neck cancer. The majority of head and neck cancers harbor amplification or overexpression of EGFR, and over 50% have mutations in TP53. These alterations can impact the DNA damage response. ATR/Chk1 and ATM/Chk2 are the two main pathways that control cellular responses to DNA damage by engaging G2/M and G1/S cell cycle checkpoints. Chk1/2 inhibitors sensitize head and neck cancer tumor cells to DNA damaging agents, such as cisplatin, cetuximab, and ionizing radiation, and potentiate DNA damage in vitro and reduce tumor growth in vivo in head and neck models. The safety and efficacy of Chk1/2 inhibition in combination with first line chemotherapy and radiation is currently being evaluated in clinical trials for advanced and metastatic head and neck cancers. In this review we will highlight the emerging molecular therapeutics targeting DNA damage response and repair checkpoints and review the available data from pre-clinical studies and on-going clinical trials.