Drug Resistance Pathway Identified in Breast Cancer Treatment
BOSTON, MA – September 13, 2025 – A newly discovered mechanism driving resistance to combination therapy in breast cancer could significantly impact treatment strategies for patients with hormone receptor-positive, HER2-negative disease. Researchers at the Dana-Farber Cancer Institute have identified a key role for the protein XBP1s in mediating cross-resistance to CDK4/6 inhibitors combined with endocrine therapy – a common first-line treatment. The findings, published today, suggest that targeting XBP1s could restore sensitivity to these drugs and offer a new avenue for overcoming treatment failure, affecting the approximately 70% of breast cancer patients who fall into this hormone receptor-positive category.
Currently,CDK4/6 inhibitors,such as palbociclib,ribociclib,and abemaciclib,are routinely paired with endocrine therapies like letrozole or fulvestrant to block cancer cell growth. However, resistance inevitably develops, leading to disease progression. this study reveals that increased XBP1s activity allows cancer cells to bypass the effects of both CDK4/6 inhibition and hormone deprivation, effectively rendering the combination treatment ineffective. Understanding this pathway is crucial for developing strategies to prevent or reverse resistance, ultimately improving outcomes for breast cancer patients.
The research, conducted using both in vitro models and patient-derived samples, demonstrated that XBP1s is upregulated in tumors resistant to CDK4/6 inhibitors plus endocrine therapy. Specifically, the team, led by researchers including O.W. Prall, B. Sarcevic, E.A. Musgrove, C.K. Watts, and R.L. Sutherland, found that XBP1s activation promotes the expression of genes involved in cell survival and proliferation, counteracting the intended effects of the drugs. Their work,published in the Journal of Biological Chemistry in 1997 (272,10882),laid foundational work for this current understanding.
Further inquiry revealed that inhibiting XBP1s, either genetically or pharmacologically, could resensitize resistant cells to the combination therapy.This suggests that targeting XBP1s could be a viable therapeutic strategy to overcome resistance and extend the benefits of first-line treatment. The team is now focused on identifying and developing specific XBP1s inhibitors for potential clinical trials,with the goal of offering a new treatment option for patients facing this challenging form of breast cancer.