Chasing the Hedgehog: Drug-Resistant BCC Still Needs Hedgehog Pathway Signaling

Smoothened mutations are responsible for about half of all resistance to vismodegib therapy for basal cell carcinoma.

Basal cell carcinomas (BCCs) appear universally dependent upon activated Hedgehog pathway signaling. This pathway is activated by loss of the receptor PTCH or activation of its downstream effector, Smoothened (SMO). Vismodegib is a small-molecule inhibitor of SMO and has been approved for the treatment of advanced BCC and basal cell nevus syndrome. While initial response rates are about 50% in advanced and metastatic BCC, resistance evolves within 6 to 8 months.

Two groups of investigators examined vismodegib resistance. Atwood and colleagues identified the mechanisms of both acquired and intrinsic resistance in this context by sequencing resistant tumors. They found that resistant tumors reactivated the Hedgehog pathway, and 85% had mutatio…

Reviewing Author

Kenneth Y. Tsai, MD, PhD

Disclosures

Grant / Research support American Association for Cancer Research – Landon Foundation; National Institutes of Health/National Cancer Institute; Cancer Prevention Research Institute of Texas

Editorial BoardsJournal of the American Academy of Dermatology

Kenneth Y. Tsai, MD, PhD

Disclosures

Grant / Research support American Association for Cancer Research – Landon Foundation; National Institutes of Health/National Cancer Institute; Cancer Prevention Research Institute of Texas

Editorial BoardsJournal of the American Academy of Dermatology

Chasing the Hedgehog: Drug-Resistant BCC Still Needs Hedgehog Pathway Signaling

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Reviewing Author