CDK4/6 inhibitors—including palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—are standard-of-care therapies for estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. While initially effective, resistance to these agents inevitably develops, limiting long-term benefit. A recent study published in NPJ Precision Oncology identifies interleukin-6 (IL-6) as a key noninvasive biomarker that predicts resistance to CDK4/6 inhibitors and highlights the IL-6/STAT3 pathway as a promising therapeutic target. The work provides preclinical evidence supporting the combination of STAT3 inhibitors with CDK4/6 inhibitors—especially in patients who progress after at least 6 months of therapy.
Photomicrograph of a breast cancer (grade 3 invasive ductal carcinoma) with frequent mitoses (mitotic figures), including a large central atypical mitosis: ©David A Litman – stock.adobe.com
In an interview with Targeted Oncology, senior author Khandan Keyomarsi, PhD, professor in the Department of Experimental Radiation Oncology at MD Anderson Cancer Center, discussed the findings and their potential clinical implications.
“The clinical trials that led to the approval of CDK4/6 inhibitors showed amazing results,” said Keyomarsi. “With estrogen receptor inhibitors alone, progression-free survival (PFS) was around 14 months. Adding CDK4/6 inhibitors increased PFS to 25 months—almost doubling it.”
However, the durability of this response remains limited. “Thirty percent of patients don’t respond to these agents at all,” she explained. “And among the 70% who do respond, 100% will eventually progress over 2 to 4 years—because these are targeted agents and resistance develops.”
The central question driving this study, led by Nicole Kettner, PhD, a postdoctoral fellow in Keyomarsi’s lab, was: What can be done for patients once resistance to CDK4/6 inhibitors develops?
Through mechanistic studies, the team identified the IL-6/STAT3/JAK signaling pathway—a key inflammatory axis—as central to acquired resistance. CDK4/6 inhibitors induce senescence in tumor cells, but resistant cells bypass this process. IL-6, a cytokine associated with the senescence-associated secretory phenotype, not only reflects this bypass but amplifies tumor aggression. “Because IL-6 circulates in the blood and because patients remain on CDK4/6 inhibitors, IL-6 levels continue to rise as cancer cells bypass senescence,” said Keyomarsi. “We hypothesized that these rising IL-6 levels—detectable in the blood—could serve as an early indicator of CDK4/6 inhibitor resistance.”
To test this hypothesis, the researchers collected blood samples from 166 patients with HR+/HER2− metastatic breast cancer, both at baseline and at radiographic progression. IL-6 levels significantly increased at progression. Moreover, in patients with longitudinal samples, IL-6 levels steadily rose prior to progression, suggesting IL-6 could serve as an early warning sign of emerging resistance. Because IL-6 can be measured using an existing clinical assay, it offers a readily translatable, noninvasive biomarker for patients on CDK4/6 inhibitors.
Supporting this hypothesis, tumor samples from the time of progression showed increased phosphorylation of STAT3 (pY-STAT3)—a downstream target of IL-6—compared to baseline (8.3% vs. 3.6%, P =.02). Importantly, there was a significant correlation between circulating IL-6 levels and tumor pSTAT3 (P =.04), further supporting IL-6/STAT3 pathway activation during resistance.
To determine whether targeting this pathway could reverse resistance, the researchers conducted functional experiments in both in vitro and in vivo models. Knocking down IL-6 in resistant cells restored sensitivity to palbociclib and endocrine therapy, while treatment with a small-molecule STAT3 inhibitor (TTI-101) effectively suppressed tumor growth in patient-derived xenografts (PDX). However, this approach was only effective in tumors from patients who had initially responded to CDK4/6 inhibitors and then progressed—suggesting the therapy is most beneficial in the setting of acquired, rather than de novo, resistance. “The 30% of patients who don’t respond to CDK4/6 inhibitors initially also don’t respond to STAT3 inhibition,” explained Keyomarsi. “This strategy only works in patients with acquired resistance—those who initially responded and then progressed.”
In parallel, current studies in the lab are pursuing another, potentially more direct and promising therapeutic strategy: targeting the IL-6 receptor itself. By blocking the receptor, elevated circulating IL-6 can be prevented from entering tumor cells and activating oncogenic transcription factors like STAT3. This upstream blockade may offer a more precise and effective method of circumventing resistance and is the focus of ongoing investigations.
While IL-6 is elevated in the majority of patients at progression, this is not universal. About 60% of progressing patients showed increased IL-6 levels, but 40% did not. To understand this divergence, the research team is now analyzing tumor tissue from both subsets of patients. “We’re actively examining the molecular differences between patients who progress with high IL-6 and those who progress with low IL-6,” said Keyomarsi. “What we’re finding is that they involve different pathways, and we’re fortunate to have inhibitors that target both.”
The team is also expanding their translational pipeline by collecting fresh tumor samples and generating patient-specific ex vivo organoid models. These models allow rapid testing of treatment strategies in real time, providing a personalized medicine approach for patients currently undergoing treatment. “These are living patients, and we’re developing treatments for them using their own tumor organoids,” said Keyomarsi. “We only test drugs that are either already in clinical trials or close to entering trials, so our work can be translated rapidly.”