PKMYT1 inhibition induces DNA damage and synergizes with immune checkpoint blockade in <i>CCNE1</i> -amplified gastroesophageal adenocarcinoma

Gastroesophageal adenocarcinoma (GEA) is an aggressive malignancy with poor prognosis and few actionable molecular alterations. <i>CCNE1</i> amplification is present in approximately 10% of patients with GEA and represents a potential therapeutic vulnerability through synthetic lethality with PKMYT1 inhibition. We demonstrate that targeting <i>CCNE1</i> -amplified GEA through PKMYT1 inhibition with lunresertib is selectively cytotoxic, induces DNA damage, and activates inflammatory signaling pathways. In a syngeneic murine model of <i>CCNE1</i> -amplified gastric cancer, we further identified that PKMYT1 inhibition induced T cell infiltration and tumor microenvironment remodeling, and synergized with anti-PD-1 therapy to drive tumor regression. Together, these results support further development of PKMYT1 inhibition in combination with PD-1 blockade for <i>CCNE1</i> -amplified GEA.