Hedgehog pathway inhibition and the race against tumor evolution

Abstract

Dependence of basal cell carcinomas and medulloblastomas on the Hedgehog pathway provides an opportunity for targeted or "personalized" therapy. The recent effectiveness and FDA approval of the first Smoothened inhibitors validates this class of agents, but has revealed drug-resistant tumor variants that bypass Smoothened inhibition. Here, we summarize the effectiveness of Hedgehog pathway inhibitors and highlight promising areas for the development of next generation drug antagonists for Hedgehog-dependent cancers.

Figure 1.

Hh pathway activation, inhibition, and mechanisms of drug resistance. (A) Diagram of inactive Hh pathway in vertebrates. (B) Hh ligand activates signaling by binding and inhibiting Ptch1, allowing Smo to suppress Sufu and activate Gli transcription factors to turn on Hh target genes. (C) Common pathway-dependent genetic mutations that lead to Hh-dependent tumors include Ptch1 inactivation, Smo activation, or inappropriate SHH expression. (D) Smo antagonists such as vismodegib suppress Hh activation to prevent tumor growth. (E) Genetic escape pathways that evolve during Smo antagonist treatment include Smo point mutations that prevent Smo–drug interaction or (F) Gli target gene amplification of Gli2 or Ccnd1. (G) Compensatory escape pathways that have evolved include inappropriate activation of S6K1 that prevents Sufu inhibition of Gli and (H) PI3K pathway up-regulation leading to inappropriate Gli activity through currently unknown mechanisms.

Figure 2.

The Smo antagonist vismodegib is an effective BCC therapy. (A) Multiple untreated, but biopsy proven, BCC tumors in an individual with a genetic syndrome leading to Shh overexpression. (B) Vismodegib-treated tumors shrink, but several resistant tumors remain after 1 yr of drug treatment. Image courtesy of A.L.S. Chang.