Decoding the association between platinum resistance and HPV status in cervical cancer using organoid models

BACKGROUND: Cervical cancer remains a leading cause of cancer-related mortality in women, with high-risk HPV types (16, 18, 31, 33, 45, 52, and 58) playing a key role in its development. Platinum-based chemotherapy is standard for recurrent or metastatic cervical cancer, but platinum resistance remains a major challenge. The link between HPV infection and platinum resistance is not well understood. Tumor organoids offer a physiologically relevant model for investigating drug resistance mechanisms in cervical cancer. RESULTS: We successfully established 37 cervical cancer organoids (CCOs), with 27 expanded for characterization and drug sensitivity testing. CCOs recapitulated the biomarker expression patterns and genomic features of their corresponding tissues. Drug sensitivity assays revealed increased cisplatin/carboplatin resistance in the non-HPV16 high-risk HPV CCOs subgroup, compared to HPV-negative CCOs. Single-cell RNA sequencing identified diverse cellular populations within CCOs, with platinum-resistant CCOs showing enhanced DNA repair, activation of the PI3K/AKT pathway, and suppressed apoptotic signaling. We also found that the PI3K/AKT inhibitor BYL719 enhanced the response to cisplatin and carboplatin in non-HPV16 high-risk HPV CCOs but not in HPV-negative CCOs. CONCLUSIONS: Cervical cancer organoids faithfully replicate the histopathological and genomic characteristics of their parental tumors, demonstrating their potential as preclinical models for studying cancer progression and drug resistance. Our findings suggest that the non-HPV16 high-risk HPV infections may contribute to increased platinum resistance through enhanced DNA repair mechanisms, increased PI3K/AKT activation and suppressed apoptosis, providing new insights for personalized cervical cancer treatment. The PI3K/AKT inhibitor BYL719 may serve as a potential therapeutic adjunct to enhance platinum efficacy in those patients with platinum-resistant cervical cancer.