Case Report: Synergistic potential of RANKL and ACLY inhibition in a breast cancer patient with acquired resistance to CDK4/6 inhibitors.

Background: The development of acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represents a major clinical challenge in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Overcoming this resistance requires novel therapeutic strategies that target the underlying molecular escape pathways. Case presentation: We report the case of a patient initially diagnosed in 2011 with pT2N0M0, ER+/HER2- invasive ductal carcinoma. Following multimodality treatment, she experienced disease progression with bone metastases after five years, followed by lymph node metastases at the ten-year mark. Subsequent treatment with the CDK4/6i ribociclib in combination with fulvestrant resulted in disease progression approximately one year later, indicating acquired resistance. Due to progressive bone loss, denosumab was initiated for skeletal support, and bempedoic acid was later added for dyslipidemia. Discussion: This case provides a clinical basis for exploring two innovative therapeutic concepts to overcome resistance. First, we discuss the complex role of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibition. Given that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) functions as a decoy receptor for RANKL, we hypothesize that a patient's LGR4 expression status may dictate the efficacy and safety of denosumab, potentially serving as a predictive biomarker to personalize its use. Second, we propose that bempedoic acid, a supportive care medication, may exert a direct anti-neoplastic effect. Its dual mechanism, inhibiting ATP-citrate lyase (ACLY) to disrupt lipid synthesis and activating AMP-activated protein kinase (AMPK) to suppress mammalian target of rapamycin complex 1 (mTORC1) signaling, positions it as a potential agent to counteract the metabolic reprogramming associated with therapeutic resistance. Conclusion: This case report illustrates the sequential development of acquired therapeutic resistance in the long-term management of metastatic breast cancer. Although a single clinical observation cannot establish definitive efficacy, this scenario generates compelling hypotheses for future studies. It highlights the potential need to explore biomarker-driven approaches-such as evaluating LGR4 expression to guide RANKL inhibition-to personalize treatment. Additionally, it raises the possibility that repurposed supportive care medications, such as bempedoic acid, might offer hypothetical anti-neoplastic benefits, warranting broader clinical validation to overcome complex resistance mechanisms.