Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma
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Hung Q. Doan1,2, Leon Chen3, Zeena Nawas4, Heng-Huan Lee5, Sirunya Silapunt2 and Michael Migden1,2,6
1 Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Dermatology, University of Texas McGovern Medical School, Houston, TX, USA
3 US Dermatology Partners, Houston, TX, USA
4 Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
5 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6 Departments of Dermatology and Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
|Hung Q. Doan,||email:||firstname.lastname@example.org|
Keywords: basal cell carcinoma; Hedgehog pathway inhibitor; resistance; switching; combination therapy
Received: July 14, 2021 Accepted: August 28, 2021 Published: September 28, 2021
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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