Document Type
Article
Publication Date
2-16-2023
Abstract
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.
Recommended Citation
Abu-Khalaf, Maysa M.; Hodge, K. Alex; Hatzis, Christos; Baldelli, Elisa; El Gazzah, Emna; Valdes, Frances; Sikov, William M.; Mita, Monica M.; Denduluri, Neelima; Murphy, Rita; Zelterman, Daniel; and Liotta, Lance, "AKT/mTOR Signaling Modulates Resistance to Endocrine Therapy and CDK4/6 Inhibition in Metastatic Breast Cancers" (2023). Kimmel Cancer Center Faculty Papers. Paper 96.
https://jdc.jefferson.edu/kimmelccfp/96
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Language
English
Comments
This article is the author's final published version in npj Precision Oncology, Volume 7, Issue 1, 2023, Article number 18.
The published version is available at https://doi.org/10.1038/s41698-023-00360-5. Copyright © The Author(s) 2023.