Effect of JAK and RIPK2 inhibition on CAF and cancer cell crosstalk

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Abstract Using deconvolution approaches, we have identified tumor-intrinsic subtypes (basal and classical) and stroma subtypes (activated and normal) in PDAC. Patient outcome is dependent on both the tumor and stroma subtype, suggesting that it is critically important to understand tumor-stroma interactions and how they affect treatment response. We have shown that cancer associated fibroblasts (CAFs) are the contributory cells in activated stroma. Similarly, we find that i/myCAF may differentially educate basal vs. classical subtype lines Our findings provide strong support for our central hypothesis that CAFs and tumor cells have interactions that together may alter tumor progression and response, making it critical that we understand the heterogeneity of the stroma, and specifically CAFs, their interaction with the tumor, for tumor-stroma context specific treatment response. We and other groups have shown that patients with basal subtype tumors are resistant to standard first-line therapies. In addition, recent results from our unbiased proteomics screen have shown that basal and classical subtype tumors are enriched in specific kinases. This diversity supplement project expands on Aim 1 in the parent U01. We have identified two small molecule inhibitors targeting JAK and RIPK2 that are sensitized by the presence of CAFs. The project will determine the role of JAK and RIPK2 signaling in the crosstalk between CAFs and tumor cells and the role of targeting JAK and RIPK2 in selected tumor and CAF subtype lines.