Targeting RB-deficient small cell lung cancer with selective CDK2 inhibition by AZD8421

Retinoblastoma (RB) loss is a hallmark of small cell lung cancer (SCLC), yet its therapeutic vulnerabilities remain underexplored. DepMap analysis identifies Cyclin-dependent Kinase 2 (CDK2) as a top vulnerability in SCLC with RB mutations and RB1 protein loss in cell lines corresponds with increased sensitivity to CDK2 KO. CDK2 is a Ser/Thr kinase activated via interaction with its cyclin partners cyclin E (CCNE) and cyclin A (CCNA), driving G1 and S phase progression of the cell cycle. Here, we demonstrate that RB-deficient SCLC exhibits sensitivity to AZD8421, a highly selective inhibitor of CDK2. Within a panel of SCLC cell lines, AZD8421 demonstrates selective growth inhibition in RB-mutant lines, with the average IC50 value being more than 45-fold lower than that observed in RB-wildtype counterparts. Mechanistically, CDK2 inhibition results in G2 cell cycle arrest and robust activation of cleaved PARP and cleaved caspase 3/7 specifically in RB-deficient models, distinguishing this cytotoxic phenotype from cytostatic effects previously observed in disease indication outside of SCLC, including CCNE1 over-expressing cancer models. In vivo, 4 RB-expressing SCLC PDX models exhibited substantial tumor growth inhibition following treatment with AZD8421, with an average TGI of 58%. In contrast, 6 RB-deficient PDX models demonstrated more profound and sustained responses with monotherapy, achieving an average TGI of 90%. Pharmacodynamic studies confirm dose-dependent target engagement via p-NPM1 suppression and evidence of apoptosis in vivo. These findings support further evaluation of CDK2 inhibition as a possible targeted strategy for RB-mutant SCLC that could offer a precision-medicine approach for a historically refractory disease subtype.