Abstract B13: Synthetic vulnerabilities in MLL3 deficient pancreatic tumors

Myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) is a histone 3-lysine 4 methyltransferase, frequently mutated in a variety of solid tumors including pancreatic ductal adenocarcinoma (PDAC), a nearly lethal disease due to our current inability to therapeutically target major oncogenic proteins driving this cancer. Like other tumor suppressor genes, direct targeting of MLL3 is not feasible, and thus our objective was to find biological pathways which are synthetic lethal targets in MLL3-deficient PDAC tumors. Identification of drug targets in such a specific genetic context could potentially dictate stratification of patients based on the mutational profile of their tumor. To achieve this, we generated a novel genetically engineered mouse model (GEMM) of pancreatic cancer, in which targeted mutation of Kras (G12D) and loss of functional MLL3 was driven by Cre-recombination from early pancreatic lineage-specific transcription factor, Pdx1. Our unpublished data suggests that loss of MLL3 function in exocrine pancreas cooperates with mutant Kras to accelerate the progression of invasive pancreatic neoplasia. Using cell lines generated from spontaneous tumors arising in KC (KrasG12D alone) and KMC (KrasG12D; MLL3/) mice, we performed functional genomic analyses and found several key oncogenic pathways upregulated in MLL3-deficient cells. We selected two well-known oncogenic pathways and through a series of cellular and biochemical assays, further validated their selectively act...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research