NEW targets in the drug development for basal cell carcinoma have been discovered by researchers from Stanford University, California, USA. This new-found knowledge of how the cancer evades currently approved drug treatments could enable a more personalised approach to therapy for patients with the condition.
The team observed that in drug-resistant cancers, one of the last proteins of the Hedgehog pathway, called GLI1, remained active. This active form of GLI1 was found in a complex with the SRF transcription factor. SRF is activated by the MKL1 protein, of which elevated levels were found in the nucleus of resistant cells compared with drug-susceptible tumours isolated from human patients.
Potential Therapeutic Pathway
In mice, the team showed that basal cell carcinomas were dramatically slowed by blocking the ability of MKL1 to increase GLI1 activity, and also that human tumours grown in the lab responded to the MKL1 blockade by reducing GLI1. These findings showcase a potential therapeutic pathway for patients who are resistant to drugs such as vismodegib, which was used in the study. This enhanced understanding of how different patients respond to certain drugs could also enable treatments to become personalised to individuals.
“People have long associated changes in the extracellular matrix with tumour progression or resistance to drugs,” commented lead author Dr Ramon Whitson, Stanford University. “But this is the first time anyone has identified the molecular causes behind this link. Now we know that we can use the presence of nuclear MKL1 as a biomarker to identify patients who might benefit more from MKL1 or GLI1 inhibitors than from vismodegib.”
Introducing new ways of treating basal cell carcinoma is vitally important because over half of newly diagnosed, advanced, or metastatic forms of the condition are resistant to currently approved drug treatments. However, many of these skin cancers do not contain any known resistance-associated mutations; this anomaly led the team to try and understand how drug treatments were being side-stepped on so many occasions.
James Coker, Reporter
For the source and further information about the study, click here.