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Chasing the Hedgehog: aPKC as a Potential Target in BCC

Summary and Comment |
March 15, 2013

Chasing the Hedgehog: aPKC as a Potential Target in BCC

  1. Kenneth Y. Tsai, MD, PhD

By regulating GLI activation, atypical protein kinase C ι/λ regulated growth of basal cell carcinomas.

  1. Kenneth Y. Tsai, MD, PhD

The role of the hedgehog (HH) pathway in basal cell carcinoma (BCC) has been well established, and the pathway is the objective of the first targeted therapy for aggressive and metastatic BCC. The PTCH gene is frequently inactivated in BCC, which leads to high HH pathway signaling, driving cellular proliferation through activation of SMO (smoothened) and GLI transcription factors. Vismodegib, recently approved for BCC, acts by inhibiting SMO. As expected, vismodegib resistance has been observed, most often as a result of pathway reactivation.

Atwood and colleagues attempted to identify additional druggable targets in the HH pathway by looking for binding partners of MIM, a scaffold protein that regulates HH signaling. They identified atypical protein kinase C ι/λ (aPKC-ι/λ) as a binding partner, but also as a potent effector of SMO, activating GLI transcription factors through phosphorylation. GLI, in turn, transcriptionally increases aPKC-ι/λ levels. This forms a feed-forward loop in which activated SMO increases aPKC-ι/λ levels and GLI activation, which further increases aPKC-ι/λ activity. As expected, higher levels of aPKC-ι/λ are found in BCCs resistant to SMO inhibitors, and inhibition of aPKC-ι/λ results in decreased proliferation of BCC cell lines and decreased tumor burden in allograft mouse models.

Comment

This important study identifies a new and potentially druggable target in hedgehog-signaling–dependent basal cell carcinoma. Inhibition of aPKC-ι/λ may be particularly useful in BCCs that have acquired resistance to vismodegib but still depend upon SMO activity.

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