Deciphering MYC-assoziated Vulnerabilities to develop pancreatic cancer subgroup-specific therapies

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Active chemotherapeutic regimens have provided a clear advance in the therapy of pancreatic ductal adenocarcinoma (PDAC). PDAC heterogeneity is one substantial hurdle to develop new therapies. Therefore, subtyping efforts aiming to connect each subtype with unique genetic, epigenetic, metabolic, signaling, or clinical features is one approach to overcome this hurdle. Two main subtypes of PDAC, the basal-like and the classical subtype, have been consistently described. Basal-like PDACs are more aggressive and seem to be resistant to currently used chemotherapies. Hyperactivation of the oncogenic transcriptionfactor MYC characterizes an aggressive subtype with overlap to basal-like PDACs. Clear evidence demonstrates that cancer with high MYC activity are dependent on genes or pathways, which can be targeted with clinical approved drugs. Therefore, a concept of synthetic lethality is suitable to target such cancers. We have defined classes of drugs able to trigger MYC-associated vulnerabilities. Based on this work we aim for: I) Our screening experiments show that inhibitors of the protein arginine methyltransferase 5 (PRMT5) are more active in PDACs with high MYC activity. Consistently, PRMT5 was found to be connected to “basal-like” cancers. We aim to find novel PRMT5 inhibitor-based combination therapies by an unbiased drug-screening experiment and characterize and validate efficacy in primary human 2D, organoids, and in vivo models. We see the potential to develop a novel therapy for a group of PDACs currently refractory to standard of care. II) Recent work shows that primary human PDAC cells upregulate the basal-like program and the MYC network in response to standard chemotherapies to become resistant. Therefore, we hypothesize that MYC activation might be a default response towards targeted and non-targeted therapies and apply to systematically investigate, whether pharmacological inhibitors targeting MYC-associated vulnerabilities that were defined in the first funding period, are also able to target chemotherapy-induced resistant PDACs. Here, we see the potential that a concept of induced vulnerability will help to address intratumoral heterogeneity and drug resistance. Such work can lead to the development of second line or sequential therapies.