Boston Children's Hospital researchers identified Fumarylacetoacetate hydrolase (FAH) as a driver of resistance to CDK4/6 inhibitors in breast cancer and published their findings in Science Advances on September 30, 2026. The study suggests that nuclear FAH could be utilized as a biomarker of resistance to these standard-of-care therapies.

Hormone receptor positive (HR+) breast cancer is the most common subtype of the disease, constituting approximately 65–75% of all breast cancer cases worldwide. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients treated with these drugs eventually develop resistance, leading to cancer cell regrowth. Up to 60% of patients derive no clinical benefit from CDK4/6 inhibitors.

A research team co-led by Naama Kanarek, PhD, and Taru Muranen, PhD, conducted the investigation. Kanarek is in the Pathology Department at Boston Children's Hospital. The group determined that FAH, an enzyme previously known only for its role in the cell's cytosol, was found in the nucleus of breast cancer cells treated with CDK4/6 inhibitors.

Inside the nucleus, FAH interacts with the cell fate regulator CDK9 and stimulates its activity. This interaction drives the resistance mechanism observed in treated cells. The researchers found that inhibiting CDK9 reverses FAH-mediated resistance, offering a potential pathway to restore drug efficacy.

The data indicate that the presence of nuclear FAH correlates with treatment failure. The data suggest nuclear FAH could be utilized as a biomarker of resistance to CDK4/6 inhibitors. This identification allows for the potential stratification of patients who may not respond to current standard therapies.

In July 2026, separate research addressed combination therapies for advanced breast cancer. Dr. Min Yan led an investigator-initiated, single-center, open-label phase Ib/II trial at Henan Cancer Hospital. The trial evaluated the triple combination of famitinib, dalpiciclib, and fulvestrant. The findings were published online in the Chinese Medical Journal on July 7, 2026.

A total of 46 eligible patients were enrolled in the Henan trial. The recommended phase II dose was established as famitinib 10 mg daily plus dalpiciclib 100 mg daily in combination with fulvestrant. In the phase II cohort of 28 patients, the confirmed objective response rate was 51.9% and the disease control rate was 92.6%. The median progression-free survival in this cohort was 15.7 months.

For context, ribociclib plus fulvestrant has shown a median progression-free survival of 20.5 months in similar patient populations. Nearly all patients in the Henan trial required dose reductions due to adverse events. The most common grade 3 or higher treatment-related adverse events were decreased neutrophil count (96.4%), decreased leukocyte count (75.0%), and decreased platelet count (10.7%). Patient enrollment was terminated early following a comprehensive benefit–risk assessment.

Yan stated that although preclinical evidence supports synergistic effects between antiangiogenic therapies and CDK4/6 inhibitors, clinical data on this combination remain limited. She noted that the objective response rate observed in the trial was numerically higher, but this did not translate into a longer progression-free survival. Yan attributed this outcome to the high rate of dose reductions necessitated by adverse events, which likely compromised dose intensity and long-term efficacy. She concluded that angiogenesis inhibitors may not represent a preferred option in the frontline treatment of HR+/HER2− breast cancer, but they may have greater potential in more aggressive subtypes like triple-negative breast cancer or refractory disease.

Another international phase III evERA trial involved 373 patients from 13 countries and examined giredestrant plus everolimus. ESR1-mutated tumors accounted for 55% of the overall population in the evERA trial. Giredestrant plus everolimus doubled median progression-free survival in advanced ER-positive breast cancer with ESR1 mutations compared to standard endocrine therapy.

Among patients with ESR1-mutated cancers, median progression-free survival increased from 5.5 months with standard endocrine therapy to 10.0 months with giredestrant and everolimus. In the overall population, giredestrant and everolimus increased median progression-free survival to 8.8 months.

The primary analysis in the ESR1-mutant group yielded a hazard ratio of 0.38 in favor of giredestrant-everolimus. The analysis of the overall population showed a 44% reduction in the progression-free survival hazard. An estimation of 18-month overall survival among patients with ESR1-mutated tumors showed 71.5% for giredestrant-everolimus and 50.9% in the control group.

Any-grade adverse events occurred in 97-99% of all patients in the evERA trial. The most common adverse events in the experimental and control arms were stomatitis (47.3% vs 48.9%), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%). The rate of fatal adverse events was 2.7% in both arms of the evERA trial.

Erica J. Mayer, MD, MPH, of Dana-Farber Cancer Institute, commented on the evERA results. She said the giredestrant-everolimus combination has the advantage of targeting two distinct signaling pathways, providing improved efficacy. Mayer added that this all-oral regimen could reduce the treatment burden by eliminating injections and reducing hospital visits.

Why It Matters

Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of hormone receptor–positive breast cancer. The identification of FAH as a driver of resistance provides a mechanistic explanation for why up to 60% of patients derive no clinical benefit from CDK4/6 inhibitors. The finding that inhibiting CDK9 reverses this resistance suggests a new therapeutic avenue for patients who fail initial treatment.

The concurrent publication of trials evaluating combination therapies illustrates the ongoing effort to overcome resistance through different mechanisms. While the Henan Cancer Hospital trial indicated limitations for angiogenesis inhibitors in frontline HR+/HER2− treatment due to toxicity, the evERA trial demonstrated significant progression-free survival benefits for an oral SERD combination in ESR1-mutated cancers. These developments collectively expand the landscape of potential interventions for advanced breast cancer subtypes.

Timeline

The findings from the Henan Cancer Hospital trial were published online in the Chinese Medical Journal on July 7, 2026. A research team co-led by Kanarek, PhD, and Muranen, PhD, published results in Science Advances on September 30, 2026. The study identified Fumarylacetoacetate hydrolase (FAH) as a driver of resistance to CDK4/6 inhibitors in breast cancer.

What's New

The study was published in Science Advances on September 30, 2026, and it was co-led by Kanarek, PhD, in the Pathology Department at Boston Children's Hospital, and Muranen, PhD. Boston Children's Hospital researchers, including Kanarek, PhD, and Muranen, PhD, identified FAH as a driver of CDK4/6 inhibitor resistance in breast cancer and published their findings in Science Advances on September 30, 2026. HR+/HER2− breast cancer constitutes approximately 65–75% of all breast cancer cases worldwide.

"Our findings suggest that angiogenesis inhibitors may not represent a preferred option in the frontline treatment of HR+/HER2− breast cancer, but they may have greater potential in more aggressive subtypes like triple-negative breast cancer or refractory disease." "These findings provide another novel therapeutic option for patients with ESR1-mutant breast cancer and may support endocrine therapy-based sequencing strategies that could delay the need for chemotherapy until later lines of treatment." Along with other positive clinical trials, including lidERA in the adjuvant setting, these results indicate the growing potential of oral SERDs to become an important endocrine therapy backbone in ER-positive breast cancer.