A method to overcome one type of drug resistance in some instances of brain or skin cancer in mice, by using an epigenetic inhibitor of the hedgehog signalling pathway, is reported online in Nature Medicine. This offers a new avenue for therapy where present drugs targeting the hedgehog signalling pathway, which drives tumour growth and development, have been hindered by emerging drug resistance.
The hedgehog signalling pathway leads to activation of the Gli proteins which in turn contribute to the signalling cascade that promotes tumour growth and development. To block hedgehog signalling, Yoon-Jae Cho and colleagues targeted the BET protein family of chromatin regulators-molecular complexes that regulate gene expression.
They found that inhibiting BET proteins with a small molecule, JQ1, could decrease expression of Gli proteins. JQ1 impaired the growth of tumours in mice that were sensitive or resistant to hedgehog pathway inhibitor drugs, suggesting that targeting epigenetic regulators of gene expression, such as the BET proteins, downstream in the pathway could be an effective adjunctive treatment for these tumours.