Computational‑experimental repurposing reveals synergistic sorafenib/hydroxychloroquine response in KRAS‑mutant breast cancer
Sorafenib‑HQ combination offers potent, context‑specific synergy for KRAS‑mutant breast cancer via Raf inhibition and autophagy blockade, enabling dose reductions and apoptosis enhancement.
KRAS mutations are found in ~25% of human cancers, with high incidence in breast and lung cancers, activating MAPK/ERK and PI3K/AKT pathways that promote proliferation, survival, and autophagy‑mediated resistance. Targeting these pathways with kinase inhibitors upregulates autophagy, reducing efficacy; therefore, combining kinase inhibitors with autophagy inhibitors offers a rational strategy. FDA‑approved sorafenib (a multi‑kinase inhibitor that targets Raf) and hydroxychloroquine (an autophagy inhibitor) were evaluated together in KRAS‑mutant MDA‑MBC‑231 breast and A549 lung cancer cell lines. Sorafenib bound Raf stably (low RMSD, ~49.9 kcal/mol MM/GBSA binding energy). IC50 values were 9.4 µM for Sorafenib and 23.6/62.4/86.2 µM for hydroxychloroquine in MDA‑MBC‑231, A549, and normal fibroblasts, respectively. The 2:1 Sorafenib:hydroxychloroquine ratio displayed strong synergy in MDA‑MBC‑231 (Combination Index = 0.32, Dose‑Reduction Index = 9.36 for Sorafenib/4.68 µM HQ at Fa = 0.5) but antagonism in A549 (CI > 1). Combination treatment enhanced late apoptosis/necrosis (49.4%) in MDA‑MBC‑231 with minimal normal‑cell cycle disruption. Sorafenib–HQ combination offers potent, context‑specific synergy for KRAS‑mutant breast cancer via Raf inhibition and autophagy blockade, enabling dose reductions and apoptosis enhancement. Tumor‑type dependence highlights the need for patient stratification; findings support repurposing with limited normal‑cell impact.
Demonstrates that an existing FDA‑approved drug pair can be rationally repurposed to overcome resistance in KRAS‑mutant breast cancer, providing a potential therapeutic strategy with reduced toxicity and improved efficacy.
Bizonyítékszint: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.
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