Targeting CCNE1 amplification in gastric cancer

Cyclin E1 (CCNE1) amplifications are found in approximately 10% of stomach cancers and are associated with DNA replication stress, chromosomal instability, therapeutic resistance, and immune cell exclusion. Recent studies found that CCNE1-amplified tumors are selectively vulnerable to loss of Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1), a member of the Wee1 G2 checkpoint kinase family that negatively regulates CDK1. PKMYT1 inhibition leads to unscheduled mitotic entry and DNA damage induction, which can trigger innate immune responses. Dr. Moy and colleagues will leverage CCNE1-amplified gastric cancer patient-derived organoids and syngeneic mouse models to investigate the activity and mechanism of combined PKMYT1 inhibition and immune checkpoint blockade. These studies aim to define a new biomarker and drug target for combination immunotherapy and targeted therapy with the potential to improve treatment options for patients with gastric cancer.