Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma

Abstract

SUMMARY Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, however, some develop resistance. Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

“…Despite the remarkable therapeutic benefits of SMOi in BCC, development of resistance, severe adverse effects and recurrence after cessation of drug treatment9, 42, 43, 44 highlight the need for novel strategies that not only focus on HH inhibition but also take into account interacting pathways modulating the oncogenicity of HH signaling.…”

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

“…The biological significance of these alterations for cell proliferation remains to be determined in these cancers. The use of Smo inhibitors for the treatment of medulloblastoma is being tested in the clinic with encouraging results (Robinson et al , 2015), but could be significantly prevented by the acquisition of resistance through secondary Smo mutations, described in basal cell carcinoma and medulloblastoma (Yauch et al , 2009; Atwood et al , 2015; Sharpe et al , 2015). In medulloblastoma, the combination of Smo inhibitors and Fbxl17 inhibitors could be a viable alternative strategy to obtain sustained responses.…”

Native <em>V. Californicum</em> Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling<strong> </strong>

“…This has been reported in many cancers, including prostate, gallbladder, pancreatic, and basal cell carcinoma [9][10][11][12]. Basal cell carcinoma (BCC) is the most common human cancer and is driven predominantly by the hyper activation of the Hh pathway [13][14][15]. For this reason, a significant number of BCC patients experience a clinical benefit from vismodegib (Erivedge®), a Smo inhibitor approved by the US Food and Drug Administration (FDA) to treat metastatic or reoccurring BCC [16].…”

“…In patients with locally advanced BCC, 43% showed a 30% decrease in visible tumour dimension, and 38% demonstrating stable tumour size. However, developed resistance to 2 of 15 vismodegib in up to 20% of advanced BCC patients within one year of treatment represents a significant limitation [15,17]. Various studies have implicated amino acid mutations in the vismodegib binding-site in Smo as a mechanism underlying acquired resistance [15,18,19].…”

“…However, developed resistance to 2 of 15 vismodegib in up to 20% of advanced BCC patients within one year of treatment represents a significant limitation [15,17]. Various studies have implicated amino acid mutations in the vismodegib binding-site in Smo as a mechanism underlying acquired resistance [15,18,19]. Due to adverse side effects and the potential for acquired resistance to vismodegib there is a continued need to investigate novel compounds that target the Hh signalling pathway, and identification of natural products that act as Hh signalling inhibitors continues to be investigated [20][21][22][23].…”