2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.02: AUTX-703, a novel and potent KAT2A and KAT2B proteint degrader, induces profound and persistent cell state differentiation and inhibits growth in SCLC Model Systems

PP01.02: AUTX-703, a novel and potent KAT2A and KAT2B proteint degrader, induces profound and persistent cell state differentiation and inhibits growth in SCLC Model Systems

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The study highlights AUTX-703, a novel, potent, and selective protein degrader targeting KAT2A and KAT2B, which has demonstrated significant potential in treating small cell lung cancer (SCLC) by affecting cell state differentiation and growth inhibition. Phenotypic plasticity, or the ability of cancer cells to alter their state, plays a pivotal role in cancer progression. The researchers used an AI/ML platform to map tumors and identify genes such as KAT2A driving oncogenic cell states.<br /><br />By applying AUTX-703 to SCLC cell lines and patient-derived organoids, notable degradation of KAT2A and KAT2B was achieved, alongside the induction of cell differentiation and growth inhibition. Notably, in the A-subtype SCLC cell line NCI-H1876, AUTX-703 treatment resulted in changed cell morphology and a shift from neural progenitor to epithelial cell state. Despite the return of KAT2A/B expression after treatment withdrawal, changes in cell state and morphology persisted, indicating a lasting impact.<br /><br />In extended studies, NCI-H1876 cells maintained epithelial differentiation, reduced neuroendocrine marker expression, and decreased MYC target gene expression well after AUTX-703 cessation. These effects were also observed in p53 and RB1 wild-type NCI-H1341 cells, suggesting the therapy's effectiveness regardless of genetic mutations.<br /><br />Treatment with AUTX-703 also enhanced immune activation and antigen presentation gene expression. In a patient-derived xenograft model, AUTX-703 facilitated a neural cell state transition, increased DLL3 expression, and reduced MYC target gene levels.<br /><br />In conclusion, AUTX-703 represents a promising therapeutic strategy targeting KAT2A/B to manipulate tumor plasticity, differentiating cells and curbing SCLC growth by reducing MYC-related gene expressions.

Asset Subtitle

Sambad Sharma

Keywords

AUTX-703

KAT2A

KAT2B

small cell lung cancer

phenotypic plasticity

AI/ML platform

cell differentiation

growth inhibition

tumor plasticity

MYC target genes