Overcoming HER2-Based Therapy Resistance in Breast Cancer Brain Metastases through CDK4/6 Inhibition
Posted October 28, 2022
Jean Zhao, Ph.D., and Nancy Lin, M.D., Dana-Farber Cancer Institute
Breast cancer brain metastases (BCBMs) are a major concern for patients with metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer, with brain metastases developing in up to 50% of cases.1 BCBMs are a significant cause of patient morbidity and mortality since effective therapies remain limited due to treatment resistance as well as challenges targeting the brain. Therefore, investigating a multidisciplinary approach may improve the current standard of care and thus prognosis for these patients. Drs. Jean Zhao and Nancy Lin from the Dana-Farber Cancer Institute previously established predictive mouse models of BCBM using patient-derived tissues. The researchers demonstrated that cyclin-dependent kinase 4 and 6 (CDK4/6), proteins which regulate cancer cell replication, are involved in resistance to HER2-targeted therapies. The tumor suppressor protein p16INK4A binds to and inhibits CDK4/6; however, it is often impaired in metastatic tumors, including breast cancer.
With support from a Fiscal Year 2017 Breast Cancer Research Program (BCRP) Breakthrough Award - Funding Level 2 - Partnering PI Option, Drs. Zhao and Lin studied the effects of combined CDK4/6 and HER2 inhibition, based on p16INK4A expression, in their BCBM mouse models. Genomic profiling revealed that p16INK4A expression was low or undetectable for the majority of the HER2+ models. When tested in mouse models of p16INK4A-negative HER2+ BCBM, combination treatment with CDK4/6 and HER2 inhibitors produced a more robust response (compared to either CDK4/6 or HER2 inhibitor alone), as demonstrated by prolonged mouse survival and marked tumor regression due to stimulation of anti-cancer mechanisms. Furthermore, the researchers found evidence suggesting the loss of p16INK4A expression contributes to the resistance of HER2-targeted therapy in BCBMs. Thus, these results suggest p16INK4A may serve as a potential biomarker to identify patients with BCBMs likely to respond to combined CDK4/6 and HER2 inhibitor treatment and overcome resistance to HER2-targeted monotherapy.
Findings from this important research identify a novel, more targeted approach with potential to support clinicians in their decision-making during treatment of patients with HER2+ BCBMs. Drs. Zhao and Lin’s research marks a promising development in the field, delivering preliminary evidence that may pave the way for a future biomarker-driven clinical trial of combined CDK4/6 and HER2 inhibition in patients with HER2+ BCBMs aimed at optimizing treatment outcomes for these patients.
Ni, Jing et al. “p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases.” Nature communications vol. 13,1 1473. 18 Mar. 2022, doi:10.1038/s41467-022-29081-2
1Pestalozzi, Bernhard C et al. “CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01).” The Lancet. Oncology vol. 14,3 (2013): 244-8. doi:10.1016/S1470-2045(13)70017-2
Last updated Friday, October 28, 2022