Resumen de Genetic determinants of atr inhibitor sensitivity and resistance in gastric cancer

Marta Jessica Llorca Cardeñosa

• Synthetic lethal approaches in identifying genetic determinants of drug response is a powerful method in selecting patents for targeted cancer therapies. Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR) is a valuable target to inhibit the DNA damage repair (DDR) pathway, that has been shown to be particularly effective in cancer cells harbouring other DDR defects, including truncating mutations in ARID1A, found in the 20% of gastric cancer (GC) patients. Although ATR inhibitors (ATRi) are emerging as promising cancer therapies, resistance mechanisms inevitably arise from these drugs as monotherapy, emphasising the importance of identifying genetic determinants of response and resistance to inform drug combinations that result in durable clinical responses.

  In this thesis, an integrated functional genomics approach was undertaken in order to identify genetic determinants to ATRi sensitivity and resistance in GC. First, I show that ARID1A defective GCs in vitro and in vivo models exhibit enhanced sensitivity to ATRi. Second, I have comprehensively identified and validated genetic determinants of ATRi-resistance by undertaking a genome-wide (GW) CRISPR/Cas9 screen and created ATRi resistant isogenic models, including CDC25B, HUWE1, CARD10, SMG8, SMG9, SMG1, HNRNPF, IRF9, and STAT2. Lastly, I have shown for the first time that mutations in the ATR FAT domain cause resistance to ATRi.

  These findings inform us about the biological mechanisms of ATRi sensitivity and resistance in GC. Furthermore, this data provides the preclinical rationale for assessing ATRi such as VX970, AZD6738 or M4344 in clinical trials, for patients with GC