Non-canonical hedgehog pathway activation by MKL1/SRF promotes drug-resistance in basal cell carcinomas

Hedgehog pathway-dependent cancers can escape smoothened (SMO) inhibition through canonical pathway mutations, however, 50% of resistant BCCs lack additional variants in hedgehog genes. Here we use multi-dimensional genomics in human and mouse resistant BCCs to identify a non-canonical hedgehog activation pathway driven by the transcription factor, serum response factor (SRF). Active SRF along with its co-activator megakaryoblastic leukemia 1 (MKL1) form a novel protein complex and share chromosomal occupancy with the hedgehog transcription factor GLI1, causing amplification of GLI1 transcriptional activity. We show cytoskeletal activation by Rho and the formin family member Diaphanous (mDia) are required for SRF/MKL-driven GLI1 activation and tumor cell viability. Remarkably, we use nuclear MKL1 staining in mouse and human patient tumors to define drug responsiveness to MKL inhibitors highlighting the therapeutic potential of targeting this pathway. Thus, our studies illuminate for the first time cytoskeletal-driven transcription as a personalized therapeutic target to combat drug resistant malignancies.