SCRMP-mediated SUMOylation of CSNK2B facilitates DNA damage repair to promote cisplatin resistance in small cell lung cancer.

Small cell lung cancer (SCLC) represents the most lethal subtype of lung carcinoma. Platinum-based agents, such as cisplatin and carboplatin, remain the cornerstone of first-line therapy for patients with SCLC, whether administered as chemotherapy alone or in combination with immunotherapy. However, patients frequently develop platinum resistance within a short time frame, leading to therapeutic failure. The molecular mechanisms underlying platinum resistance in SCLC require further investigation, given that effective intervention strategies remain elusive. Through multiomic analysis integrating transcriptomic data from cisplatin-resistant PDX tissues and the IMpower133 SCLC cohort study and translatomic data from SCLC cells, we identified a platinum resistance-associated noncanonical open reading frame derived from MIR7-3HG. This noncanonical ORF encodes an unannotated 128-amino acid protein, designated SCRMP (SCLC cisplatin resistance-associated microprotein). SCRMP was up-regulated in cisplatin-resistant SCLC tissues and cell lines, and its elevated expression strongly correlated with impaired platinum response and unfavorable survival outcomes in patients. CRISPR-Cas9-mediated SCRMP knockout restored cisplatin sensitivity and promoted apoptosis in SCLC cells, platinum-resistant patient-derived organoids in vitro, and patient-derived xenografts in vivo. Mechanistically, SCRMP potentiated platinum resistance by mediating SUMOylation and nuclear translocation of CSNK2B, which stabilized the RBBP4-p300 complex. This stabilization activated transcription of RAD51C and associated DNA damage repair genes through histone acetylation, ultimately promoting therapeutic resistance. Our study systematically elucidates the biological function of SCRMP in SCLC platinum resistance and delineates its specific molecular mechanism in regulating DNA damage repair, thereby providing theoretical foundations and potential intervention strategies for overcoming platinum resistance in SCLC.