Why do some patients with basal cell carcinoma become resistant to vismodegib?

View:590 Time:2018-02-07

Basal cell carcinoma (BCC) is the most common type of skin cancer, accounting for approximately 80% of all skin cancers. In addition, BCC is also one of the most common human cancers and its incidence is rising globally. BCC arises in basal cells, the small, round cells found in the lower part of the epidermis (the outer layer of the skin). BCC can be cured. The earlier the diagnosis, the higher the cure rate. However, advanced BCCs often prove resistant to treatment and may lead to cancer-related death.

Over the past several decades, scientists have been making progress in understanding the molecular pathogenesis of BCC. Now, it's clear that BCC is often associated with mutations in hedgehog pathway genes, especially PTCH1 and SMO. The Hedgehog pathway plays key roles in normal embryonic development as well as in adult tissue maintenance, renewal and regeneration. In addition to BCC, malfunction of Hedgehog signaling is also seen in many other cancers.

The vast majority of patients with BCC show overactive Hedgehog signaling. Therefore, inhibiting hedgehog signaling has been explored as a therapeutic strategy for BCC. In 2012, the first Hedgehog inhibitor -- vismodegib -- was approved by FDA for treatment of advanced BCCs. However, some BCC patients are resistant to vismodegib. What causes this resistance? Scientists ask.

A study now provides insights into this question. In the study, the researchers performed multidimensional genomics analysis of human and mouse drug-resistant BCCs. They discovered that a protein called GLI1, which is a component of the Hedgehog pathway, stayed active in the resistant cancers. In addition, they identified increased concentrations of another protein called MKL1 in the nucleus of resistant cancer cells. Furthermore, inhibition of MKL1 suppressed BCC growth in mice. Experiments in human tumors grown in the lab suggested that MKL1 inhibition suppressed tumor growth by reducing GLI1 activity.

The study would help explain why some BCC patients become resistant to the Hedgehog inhibitor vismodegib. It may be associated with alterations in GLI1 activity and the presence of nuclear MKL1. Further, these discoveries would be employed to develop novel treatments for BCC.

The full paper (Noncanonical hedgehog pathway activation through SRF–MKL1 promotes drug resistance in basal cell carcinomas) can be read in the journal Nature Medicine.

The study was carried out by researchers from Stanford University School of Medicine and Children's Hospital Oakland Research Institute. Prof. Anthony Oro is the senior author. The research interests of Prof. Oro include cancer genomics and tumor evolution, stem cell biology and hair/skin development and regeneration, and definitive molecular and cellular therapeutics.
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