Targeting MICAL2 For Pancreatic Cancer Therapy

Novel Approaches, Targets, and Therapeutics; Childhood Cancers

Andrew Lowy, MD (UC San Diego)

Herve Tiriac, PhD (UC San Diego)

Susanne Heynen-Genel, PhD (Sanford Burnham Prebys)

Pancreatic cancer (PC) is lethal, treatment-resistant and marked by a KRAS-driven, immune-cold stroma. MICAL2 is overexpressed in >75% of PCs and drives MRTF/SRF transcription. Overexpression predicts poor survival, and boosts KRAS, RTK and EMT signaling. MICAL2 knock-down (KD) reduces cancer-associated fibroblasts and extracellular matrix, and recruits cycling, granzyme-rich CD8 T cells. CD8 depletion restores tumor growth, and adoptive transfer of MICAL2-KD-derived T cells shrinks tumors, demonstrating immune-mediated control. Large PC tumors regress in an inducible MICAL2-KD system demonstrating the power of this therapeutic approach. Thus, MICAL2 links oncogenic KRAS to desmoplasia and immune exclusion, and dual KRAS/MICAL2 targeting may yield durable, immune-potentiated responses. The MICAL2-MRTF-SRF transcriptional axis has never been targeted clinically, and the available tool compounds show sub-therapeutic potency. Here, we will identify and test novel MICAL2 inhibitors.