Hedgehog pathway–dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF–MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.
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The authors wish to thank all members of the laboratory of A.E.O. and the Stanford Dermatology Department for suggestions and guidance. Specifically, the authors would like to thank S.P. Melo for guidance and assistance with ChIP–seq analyses. This work was funded by the V Foundation Translational Award, National Cancer Institute (R01CA157895), the National Institute of Arthritis and Musculoskeletal Disease (R01AR04786 and 5ARO54780), the Stanford Epithelial Biology Training Grant award to R.J.W. (T32-AR007422), National Institutes of Health (NIH) Pathway to Independence Award to S.X.A. (4R00CA17684703), and a Damon Runyon clinical investigatory award (J.Y.T.). The Stanford Cell Sciences Imaging Facility provided instrumentation and technical assistance for microscopy using a Leica SP8 confocal microscope funded by a National Center for Research Resources grant (1S10OD010580). The Stanford functional Genomics Facility provided sequencing services for ASZ RNA-seq and SRF ChIP–seq using the Illumina HiSeq 4000 platform purchased using an NIH S10 Shared Instrumentation Grant (S10OD018220).
A.E.O. is a clinical investigator funded by Novartis.
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Whitson, R., Lee, A., Urman, N. et al. Noncanonical hedgehog pathway activation through SRF–MKL1 promotes drug resistance in basal cell carcinomas. Nat Med 24, 271–281 (2018). https://doi.org/10.1038/nm.4476
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