Overcoming Resistance to CDK4/6-targeted Therapy Using JAK2/STAT3 Inhibitor in Triple-Negative Breast Cancer

Breast cancer is the most common type of cancer diagnosed in women, with nearly 30% of cases becoming metastatic accounting for over 90% of breast cancer-related deaths. Among different breast cancer subtypes, triple-negative breast cancer (TNBC) has the worst prognosis and the highest propensity to metastasize. However, TNBC patients have limited treatment options due to their lack of actionable drug targets while therapeutic resistances result in high rates of recurrence and metastasis. Cyclin-dependent kinase 4 and 6 (CDK4/6) are major cell cycle regulators that control G1 to S phase transition and aberrant hyperactivation of the CDK4/6 pathway results in uncontrolled cell proliferation. Although three CDK4/6 inhibitors (CDK4/6is) have achieved clinical benefits in HR+/HER2- advanced and metastatic breast cancer, none of them is approved for TNBC due to its low efficacy. Herein, we demonstrate that the interleukine-6 (IL-6)/Janus kinase 2 (JAK2)/signal transducer and activation of transcription 3 (STAT3) signaling pathway is significantly correlated with CDK4/6i resistance signature in breast cancer, and its co-activation with CDK4/6 pathway is significantly enriched in TNBC patients. Together with the consistent in vitro and in vivo observations showing that FDA-approved CDK4/6i Abemaciclib (Abe) inadvertently activates STAT3 in TNBC, we proposed a novel treatment regimen by combining Abe with an FDA-approved JAK2-specific inhibitor Fedratinib (Fed) to enhance Abe’s efficacy in TNBC. For the first time, our study demonstrated the combinatorial effects of Abe and Fed against TNBC in vitro and in vivo, and elucidated the mechanisms underlying the combination synergy, i.e., inducing apoptosis, promoting G2/M arrest, reducing cellular senescence, suppressing cancer stemness, and attenuating multi-organ metastases. These preclinical findings could pave the foundation for eventual clinical evaluation of a novel combination therapy with two FDA-approved small molecule inhibitors for TNBC patients.