AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers.

Abu-Khalaf, Maysa M.; Alex Hodge, K.; Hatzis, Christos; Baldelli, Elisa; El Gazzah, Emna; Valdes, Frances; Sikov, William M.; Mita, Monica M.; Denduluri, Neelima; Murphy, Rita; Zelterman, Daniel; Liotta, Lance; Dunetz, Bryant; Dunetz, Rick; Petricoin, Emanuel F.; Pierobon, Mariaelena

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.

UNITED States. Food & Drug Administration; METASTATIC breast cancer; HORMONE therapy; HORMONE receptor positive breast cancer; EPITHELIAL tumors; DISEASE progression

NPJ Precision Oncology, 2023, Vol 7, Issue 1, p1

2397-768X

Academic Journal

10.1038/s41698-023-00360-5