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

Abstract

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.

Prediction of Diagnostic Gene Biomarkers Associated with Immune Infiltration for Basal Cell Carcinoma

“…Immunotherapy is promising for cancer treatment and has revolutionized the eld of tumor immunology. Hedgehog pathway inhibitors (HHIs) are often used as drug targets for patients with advanced BCC; however, some patients develop resistance [29]. Thus, the development of new treatment strategies is necessary.…”

Non-surgical Management of Locally Advanced Basal Cell Carcinoma of the Upper Extremity With Vismodegib

“…Median relapse-free survival was reported as 18.4 months; most patients who experienced relapse still responded to a vismodegib rechallenge [ 15 ]. Switching hedgehog inhibitors may also benefit patients with resistant BCC [ 16 ].…”

Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives

“…As shown previously, vismodegib and sonidegib are effective drugs for the treatment of laBCC. However, some patients may be resistant to treatment, termed intrinsic resistance, or may develop resistance to treatment after the initial response, termed acquired resistance [ 50 ]. Numbers of acquired resistance on HHIs are not known from pivotal studies, but the occurrence of intrinsic and acquired resistance was investigated in a subset of 148 patients of the STEVIE study [ 51 ].…”