Abstract 1449: The MAPK pathway regulates cellular identity in lung and pancreatic adenocarcinoma

Abstract Recently published data from our lab indicates that downstream signaling from oncogenic KRAS can alter the differentiation state of NKX2-1-negative lung adenocarcinoma (LUAD), a subtype of lung cancer with a foregut-like identity similar to classical pancreatic ductal adenocarcinoma (PDAC). In NKX2-1-negative LUAD, inhibition of the MAPK pathway induces a FoxA1/2-dependent lineage switch marked by the down regulation of gastric surface mucosal epithelium markers and induction of genes associated with zymogenic chief cells of the stomach. We used a pharmacological approach to investigate whether MEK/ERK signaling regulates the differentiation state of classical PDAC. Treatment of murine PDAC organoid lines with a MEK inhibitor led to the induction of zymogenic chief cell markers. Further analyses showed that the deletion of either Foxa1/2 or Hnf4α blocked the induction of chief cell transcripts in response to MEK inhibition. Moreover, exogenous expression of FoxA1/2 revealed that the expression of FoxA1/2 alone was sufficient to rescue MEK inhibitor-induced chief cell programming in genetically FoxA1/2-null organoids. This prompted the hypothesis that the genomic localization and activity of FoxA1/2 and HNF4α are regulated by MAPK signaling in PDAC. To elucidate the mechanisms by which FoxA1/2 and HNF4α activate the zymogenic chief cell program in PDAC in response to MAPK pathway inhibition, we treated KRAS-driven, P53-null murine PDAC organoids with various MEK inhibitors. We then performed ChIP-seq for FoxA1/2 and HNF4α on these organoid lines with pharmacological MEK/ERK manipulation to determine whether MEK/ERK activity modulates binding FoxA1/2 and HNF4α to zymogenic chief targets, facilitating this lineage switch. The evaluation of FoxA1/2 binding patterns and differential binding analysis revealed no direct binding of FoxA1/2 and chief cell targets of interest in these PDAC organoids upon MEK/ERK inhibition. This suggests that the induction of the chief cell lineage switch may not be directly orchestrated by FoxA1/2 relocalization but by alternative methods. We are currently investigating potential indirect mechanisms by which FoxA1/2 and HNF4α induce this lineage switch using ChIP-seq and ATAC-seq. Citation Format: Sydney N. Larsen, Walter Orellana, Katherine Gillis, Eric Snyder. The MAPK pathway regulates cellular identity in lung and pancreatic adenocarcinoma [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 1449.