Abstract 3037: Targeting pro-survival MYC oncogene expression in small cell lung cancer and large cell neuroendocrine carcinoma of the lung with a novel small molecule PIM2 inhibitor
Authors: Katherine G. Minton, Anthony H. Cuadros, Olivia C. Terry, Phu D. Pham, Mateusz Opyrchal, Kelvin P. Lee, Misty D. Shields
Journal: Cancer Research (2025)

Introduction: Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma of the lung (LCNEC) are aggressive neuroendocrine carcinomas (NECs) that exhibit frequent chemoresistance and lack effective treatments for relapsed disease. MYC paralogs are frequently amplified on extrachromosomal DNA in lung NECs. Recent interrogation into the evolution of SCLC has identified c-MYC amplification as a major driver of tumor plasticity across the neuroendocrine spectrum. As such, targeting molecular underpinnings related to MYC amplification provides a therapeutic vulnerability for lung NECs. JP11646, a potent non-ATP competitive inhibitor of PIM family members that function to phosphorylate Ser329 on c-MYC, has preclinical efficacy in a number of cancers including triple negative breast cancer and multiple myeloma. Here, we investigate the efficacy and functional effects of JP11646 in lung NECs. Methods: JP11646 sensitivity was evaluated in triplicate with eight serial dilutions for 72 h (hours). The transient effects of JP11646 after 24 h were evaluated in H1155, H524, H209, and H1417, which represent the spectrum of MYC paralog amplification in lung NECs, through RNAseq. Protein expression was evaluated via western blot analysis (PIM2 1:1000). PIM2 RNA interference (50 nM) was performed to investigate effects on JP11646 sensitivity and interactions between PIM- and MYC- paralogs after 72 h. Results: A panel of MYC paralog amplified cell lines differentially express PIM2 and exhibit nanomolar potency for JP11646 (IC50: mean 87 nM, range 7 - 117 nM). Transient knockdown of PIM2 results in reductions in PIM3 and l-MYC in H209. Following 24 h JP11646 treatment, we find that cells exhibit reduction of PIM2 and MYC paralogs and extensive downregulation of oncogenes including amplified MYC paralogs and AURKA. Interestingly, a pattern of upregulation of reciprocal MYC paralogs is observed in H1155, H209, and H1417. Insignificant changes are observed in PIM family expression with 24 h JP11646 treatment. After 72 h, we find that PIM2 knockdown further enhances JP11646 sensitivity in H1155, reducing IC50 two-fold. Conclusion: Given the observed reduction of PIM2 protein levels following treatment, we hypothesize that JP11646 functions through a feedback mechanism, disrupting PIM2:MYC interactions to reduce MYC paralog RNA/protein expression in lung NECs and exert its anticancer effects. Future studies are underway to further examine the mechanism and preclinical effects of JP11646, including xenograft studies, proteasome inhibitor studies, and CRISPR knockout of PIM2. Citation Format: Katherine G. Minton, Anthony H. Cuadros, Olivia C. Terry, Phu D. Pham, Mateusz Opyrchal, Kelvin P. Lee, Misty D. Shields. Targeting pro-survival MYC oncogene expression in small cell lung cancer and large cell neuroendocrine carcinoma of the lung with a novel small molecule PIM2 inhibitor [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 3037.