KiP analysis of ER+ Breast Cancer

Endocrine therapies (ET) combined with CDK4/6 inhibition (CDK4/6i) is standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however lethal drug resistance is common. Proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is highly estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2 independent. In clinical samples, high PKMYT1 mRNA is a resistance biomarker for both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib(RP-6306) and gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53 in vitro; the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. These results demonstrate the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6i resistant TP53 mutant ER+ breast cancer.