Abstract 6384: CD24 promotes development of <i>KRAS</i>-mutant lung adenocarcinoma and response to <i>KRAS</i>-targeted therapy

Abstract KRAS-mutant lung adenocarcinoma (KM-LUAD) is the most common molecular subtype of lung cancer with poor clinical outcomes even at early stages. Although KRAS inhibitors have offered therapeutic benefits, most patients develop resistance due to poorly understood mechanisms. We previously reported by single-cell RNA sequencing (scRNA-seq) that CD24, a “do not eat me” signal, was significantly elevated in tumor cells of early-stage LUADs compared to matched normal tissues. CD24 was central to tumor-immune interactions, positively correlating with immunosuppressive programs. We were thus prompted to evaluate CD24 expression patterns during early LUAD development. In Gprc5a-/- mice exposed to tobacco-carcinogen (NNK), we found elevated Cd24a in Krt8+ alveolar intermediate cells (KACs), that we recently characterized as progenitors for KM-LUAD, and in tumor cells during early LUAD development. Human scRNA-seq data from a unique cohort of matched normal tissues, premalignant lesions, and LUADs corroborated these findings, showing increased CD24 in premalignant and malignant cells compared to normal alveolar subsets, with prominent elevation in KACs. We then examined the functional relevance of targeting CD24 in KM-LUAD. Targeting CD24 via CRISPR/Cas deletion or neutralizing antibodies significantly reduced tumor growth in a syngeneic KM-LUAD model, associated with upregulation in genes linked to augmented T-cell responses and increased phagocytosis of tumor cells. Given CD24’s elevated expression in KM-LUAD progenitors and its impact on tumor growth and immune phenotypes, we examined its expression in the context of KRAS-targeted therapy. Treatment with the KRASG12D inhibitor MRTX1133 led to dose-dependent increases in Cd24a levels in multiple mouse KM-LUAD cell lines harboring KRAS p.G12D mutations. Analysis of publicly available datasets showed that KRASG12C inhibitor MRTX1257 also increased Cd24a expression in mouse tumor cells with KRAS p.G12C mutations. In syngeneic mice with KrasG12C/+;Tp53R172H/+ KM-LUAD cells, sotorasib treatment enhanced CD24 protein levels in tumors compared to controls. Thus, we examined effects of combined inhibition of CD24 and KRAS. Syngeneic mice treated with MRTX1133 and anti-CD24 antibodies showed greater KM-LUAD reduction than single agents or controls. NNK-exposed Gprc5a-/- mice receiving both therapies exhibited fewer lesions and markedly enhanced tumor immune infiltration compared to single agents or controls. Similarly, combining KRASG12C inhibitor adagrasib with anti-CD24 antibody in syngeneic mice reduced KM-LUAD growth more than single treatments or controls. Our findings demonstrate that CD24 drives KM-LUAD progression from its earliest stages and contributes to adaptive resistance to KRAS inhibition. Targeting CD24 in combination with KRAS inhibitors, represents a promising strategy for treating and intercepting KM-LUAD. Citation Format: Zahraa Rahal, Sujuan Yang, Minyue Chen, Inti Tarifa Reischle, Teng Zhou, Tieling Zhou, Lorena I Gomez Bolanos, Alejandra G Serrano, Ansam Sinjab, Jiping Feng, Luisa Maren Solis Soto, Ignacio Ivan Wistuba, Haniel A Araujo, Ferdinandos Skoulidis, Humam Kadara. CD24 promotes development of KRAS-mutant lung adenocarcinoma and response to KRAS-targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6384.