Vismodegib resistant mutations are not selected in multifocal relapses of locally advanced basal cell carcinoma after vismodegib discontinuation

Ighilahriz, Meriem; Benfodda, M.; Sharpe, Hayley J.; Soufir, Nadem; Dumaz, Nicolas; Battistella, Maxime; Savina, Ariel; Bouquet, Fanny; Nikolaev, Sergey I.; Basset-Séguin, Nicole

doi:10.1111/jdv.15741

Cited by 1 publication

(1 citation statement)

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“…Interestingly, in a study of three patients with laBCC who had complete response following treatment with vismodegib that was clinically and histologically confirmed, and then relapsed after discontinuing treatment, mutational analysis of the coding regions of sequenced genes in relapsed tumors was not significantly changed compared with tumor analyses prior to vismodegib treatment [ 81 ]. These results demonstrate that tumor relapse following vismodegib discontinuation retains the same mutational pattern as the baseline tumor, suggesting these tumors may be eligible for treatment rechallenge [ 81 ].…”

Section: Introductionmentioning

confidence: 99%

Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma

Doan

Chen²,

Nawas

et al. 2021

Oncotarget

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Although basal cell carcinoma (BCC) is often managed successfully with surgery, patients with locally advanced BCC (laBCC) or metastatic BCC (mBCC) who are not candidates for surgery or radiotherapy have limited treatment options. Most BCCs result from aberrant Hedgehog pathway activation in keratinocyte tumor cells, caused by sporadic or inherited mutations. Mutations in the patched homologue 1 gene that remove its inhibitory regulation of Smoothened homologue (SMO) or mutations in SMO that make it constitutively active, lead to Hedgehog pathway dysregulation and downstream activation of GLI1/2 transcription factors, promoting cell differentiation and proliferation. Hedgehog inhibitors (HHIs) block overactive signaling of this pathway by inhibiting SMO and are currently the only approved treatments for advanced BCC. Two small-molecule SMO inhibitors, vismodegib and sonidegib, have shown efficacy and safety in clinical trials of advanced BCC patients. Although these agents are effective and tolerable for many patients, HHI resistance occurs in some patients. Mechanisms of resistance include mutations in SMO, noncanonical cell identity switching leading to tumor cell resistance, and non-canonical pathway crosstalk causing Hedgehog pathway activation. Approaches to managing HHI resistance include switching HHIs, HHI and radiotherapy combination therapy, photodynamic therapy, and targeting Hedgehog pathway downstream effectors. Increasing understanding of the control of downstream effectors has identified new therapy targets and potential agents for evaluation in BCC. Identification of biomarkers of resistance or response is needed to optimize HHI use in patients with advanced BCC. This review examines HHI resistance, its underlying mechanisms, and methods of management for patients with advanced BCC.

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Section: Introductionmentioning

confidence: 99%