Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers

Abstract

Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.

Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells

“…Inhibition of Wee1 by adavosertib was recently described as a highly effective single-agent treatment for HPV-positive HNSCC dependent on FOXM1 activation ( 55 ) and single agent radio- and chemosensitization through PARP, as well as through intra-S/G2 checkpoint inhibition, which was repeatedly demonstrated in HPV-positive HNSCC models ( 10 , 21 – 23 , 25 , 30 , 31 , 56 , 57 ). In this study we demonstrate a highly effective radiosensitization of HPV-positive HNSCC cells using dual inhibition of PARP and the S/G2 cell cycle checkpoint in five and moderate radiosensitization in one out of six cell lines tested.…”

“…We and others have demonstrated that PARP inhibition as well as inhibition of radiation induced cell cycle checkpoints via targeting of Chk1, ATR, or Wee1 can radiosensitize HPV-positive HNSCC cells (10,(21)(22)(23)(24)(25). Different mechanisms may account for the observed sensitization.…”

HGF/MET Signalling and DNA Damage Response: Strategies to Conquer Radiotherapy Resistance in Head and Neck Cancer

“…Because CHK1 has been proposed to be a promising target in HNSCC cell cycle regulation, and recent HNSCC studies have shown ATR inhibition to sensitise HPVnegative cells to DDAs, our assumption is encouraging [125,139]. Moreover, other studies have shown synthetic lethal targeting to sensitize HNSCC cells to DDAs with other inhibitors [137,140,141]. Because of this, applying c-MET inhibitors in a synthetic lethal manner could provide an alternate approach for HPV-negative HNSCCs.…”

“…Conceptually, the loss of wild type p53 can be exploited therapeutically by inducing synthetic lethality [135]. By abrogating the G2 checkpoint, mutant or depleted TP53 cells could be sensitised to DDAs -this is because the absence of both G1 and G2 checkpoints cause the segregation of chromosomal aberrations, forcing cells into the M phase to die [136,137]. As stated, in the previous section, in 2010 Medova et al, reported c-MET inhibition to attenuate the ATR-CHK1-CDC25 pathway -responsible for intra-S and G2-M arrest [77].…”

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

“…M6620 (previously VX-970) is a first-in-class ATR inhibitor currently under investigation in a phase 1 trial in HPV-negative HNSCC (NCT02567422). AZD6738 is another selective ATR inhibitor that was recently demonstrated to enhance radiotherapy response in both HPV-negative and HPV-positive HNSCC in vitro [62]. A clinical trial of AZD6738 plus olaparib is currently ongoing in HNC (NCT02264678), and another biomarker-based study has recently been completed (NCT03022409).…”