Dr Arteaga on CDK4/6 Inhibitor Resistance in ER+ Breast Cancer

Carlos Arteaga, MD, director, University of Texas (UT) Southwestern Harold C. Simmons Comprehensive Cancer Center, the Lisa K. Simmons Distinguished Chair in Comprehensive Oncology, associate dean of Oncology Programs, UT Southwestern Medical Center, discusses resistance to CDK4/6 inhibitors in patients with estrogen receptor (ER)–positive breast cancer.

Although CDK4/6 inhibitors have demonstrated efficacy in patients with HR-positive breast cancer and have prolonged quality of life for those in the advanced setting, they do not provide a curative outcome. Consequently, patients eventually experience resistance and disease progression, necessitating alternative therapeutic approaches, Arteaga explains.

More research is required to better understand the mechanisms of resistance to CKD4/6 inhibitors; however, Arteaga notes that the loss of the retinoblastoma (RB1) tumor suppressor has been implicated in resistance to these agents. Research published in Nature Communications in March 2024 delved into potential treatment approaches following loss of RB1 function, and the study highlighted the potential for targeting PRMT5 in patients who develop CKD4/6 inhibitor resistance. Arteaga explains that approximately 10% of patients who develop resistance to CDK4/6 inhibitors experienced a loss of RB1.

As CDK4/6 inhibitors continue to gain prominence as first-line therapies globally, the population of patients experiencing resistance due to RB1 loss and PRMT5 activation is expected to rise, Arteaga continues. To address this, Arteaga notes that clinical development of PRMT5 inhibitors is underway, and in the published research, Arteaga and colleagues noted that treatment with the PRMT5 inhibitor pemrametostat (GSK3326595) and fulvestrant (Faslodex) synergistically inhibited the growth of ER-positive/RB-deficient cell-derived and patient-derived xenografts.

These findings offer a potential basis for developing targeted therapeutic strategies, Arteaga continues. By targeting PRMT5, clinicians may be able to overcome resistance and improve outcomes for patients with CDK4/6 inhibitor–resistant breast cancer. The identification of PRMT5 as a key player in CDK4/6 inhibitor resistance underscores the importance of understanding molecular mechanisms driving treatment failure, Arteaga concludes.