Théodora Kipers

Introduction. Basal cell carcinoma (BCC) makes up about 80 percent of all skin cancers, and patients most commonly diagnosed are of Caucasian in origin.¹ Although BCC rarely metastasizes, it still poses a significant health hazard because of the large number of individuals diagnosed each year and the extensive morbidity caused by local invasion and cell destruction.¹ When BCC metastasizes, the prognosis is poor with a median survival rate of 87 months with regional and 24 months with distant metastatic disease.² The most common genetic mutations in BCC are in the Hedgehog receptor patched 1 (PTCH1) and cell cycle regulator TP53 which are predominately from UV exposure.¹ Common mutations in PTCH1 block protein maturation that results in elimination of its function to block the Hedgehog pathway; however, the degree of impairment depends on the mutation-type.¹ The silencing of PTCH1 results in increased expression of the smoothened protein and the downstream Hedgehog pathway transcription factor GLI1.³ Despite therapies to turn off the Hedgehog pathway and prevent the increased expression of the smoothened protein, basal cell carcinomas continue to persist and cause morbidity. Methods. A mouse model was used in which Ptch1 was inactivated in basal skin cells, resulting in BCC.⁴ Subjects were treated for 28 days with Vismodegib,⁴ which inhibits the Hedgehog pathway by blocking smoothened.¹ It is approved for the treatment of locally advanced and metastatic basal cell carcinoma.⁴ Results. After 28 days of treatment, residual tumors remained but these tumors did not express the Hedgehog target gene GlI1.⁴ It was determined that the residual BCCs in mice were quiescent during treatment and did not require active Hedgehog signaling to survive.⁴ These BCCs also reinitiated tumor growth upon cessation of drug treatment.⁴ These tumors did not acquire drug resistance, but instead had found a way to bypass the Hedgehog pathway.⁴ When treatment was discontinued, the tumors reactivated the Hedgehog pathway and continued to grow.⁴ The WNT pathway was important in this cell identity switch through reprogramming of super-enhancers that drive the expression of critical transcription factors.⁴ Although WNT is required for BCC formation, it is turned off in activated tumors⁴ and reactivated in residual tumors.⁴ When Vismodegib and a WNT pathway inhibitor were both used in tumor treatment, there was a 33 percent decrease in the number of residual tumors as compared to the use of Vismodegib alone.⁴ Conclusion. Despite treatment with a Hedgehog pathway inhibitor in PTCH1-mutated BCC, some tumors continue to exist. By using a combined treatment of a Hedgehog pathway inhibitor and a WNT inhibitor, the rate of a complete response to anti-tumor therapy may be increased.⁴ This may help the overall prognosis of patients with metastatic BCC.

1. Maturo MG, Rachakonda S, Heidenreich B, et al. Coding and noncoding somatic mutations in candidate genes in basal cell carcinoma. Sci Rep. 2020;10(1):8005.
2. Verkouteren BJA, Wakkee M, van Geel M, et al. Molecular testing in metastatic basal cell carcinoma. J Am Acad Dermatol. 2019.
3. Rahman MM, Hazan A, Selway JL, et al. A Novel Mechanism for Activation of GLI1 by Nuclear SMO That Escapes Anti-SMO Inhibitors. Cancer Res. 2018;78(10):2577-2588.
4. Biehs B, Dijkgraaf GJP, Piskol R, et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature. 2018;562(7727):429-433.