Hedgehog Pathway Inhibitors: Clinical Implications and Resistance in the Treatment of Basal Cell Carcinoma.

Suzanne Habashy,Stacey E Heindl,Aliya Jafri,Hiba O Osman,Somtochi Udekwe,Neena E Thomas

doi:10.7759/cureus.13859

Abstract

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer and is on the rise. Most BCCs are benign; however, a very small percentage are locally advanced and metastatic. The pathway that normally regulates cell growth and proliferation is directed by the hedgehog pathway (HP). In BCC, it becomes over-stimulated due to genetic abnormalities. Treatments for BCC include local treatment by cryotherapy (liquid nitrogen), topical immunosuppression, surgery, or radiotherapy. Systemic treatment may be required in locally advanced lesions, metastatic BCC, or individuals who are inoperable.The systemic treatments of BCC act to inhibit the HP and are called hedgehog pathway inhibitors. The first one being vismodegib and the second sonidegib.Although these treatments have shown promising results, they have prominent side effects in almost all patients, with few patients having to discontinue the treatment. About 50% of patients did not respond to treatment from the beginning, some had partial responses, others had recurrence after discontinuing the drugs, and few had worsening of the disease. In this paper, we will explore the most common side effects, resistance, and different methods to overcome resistance to ensure the highest rate of cure for BCC.

Highlights

BackgroundSkin cancer is the most common malignancy worldwide, with 3.5 million people diagnosed with nonmelanoma skin cancer (NMSC) each year
We explore the use of hedgehog pathway inhibitor (HPI) in terms of their pathway mechanisms, side effects, tolerability, resistance, and methods to maximize their effects
At one year, updated objective response rate (ORR) increased from 30.3% to 33.3% in MBCC and from 42.9% to 47.6% in LBCC

Summary

Introduction

Skin cancer is the most common malignancy worldwide, with 3.5 million people diagnosed with nonmelanoma skin cancer (NMSC) each year. The efficacy and long-term safety of HPIs have been studied and explored, resulting in guidelines for the treatment and follow-up of patients regarding side effects, toxicity, tolerability, and quality of life [5] Due to these inquiries about the drugs in question, resistance and poor or partial response to HPIs have been noted, mostly from gene mutations of the PTCH, the smoothened head (SMO), or bypassing the HPs entirely [6]. Pre-treatment genetic testing is recommended to determine patients with possible resistance who might not benefit from HPI and can protect patients from side effect exposure and toxicity [16] This genetic testing may give us an idea about combination therapy to control tumor growth [15]. The re-introduction of the HPI can achieve the same previous clinical response [4]

Conclusions

Findings

Disclosures