Dual drug approach effective in ‘untreatable’ melanoma

By Michael Woodhead

31 Mar 2021

A combination of epigenetic drugs may be the next hope for melanoma patients who do not respond favourably to current treatments such as immunotherapy, Australian researchers say.

Dual use of BET and CDK9 inhibitors has been shown to synergistically kill melanoma cells and had potent anti-tumour activity, according to in vivo and in vitro studies carried out at the Centenary Institute, Sydney.

Reporting their findings in the Journal of Investigative Dermatology the researchers said dysregulation of epigenetic modifier BET and CDK9 proteins played a key role in melanoma biology including resistance to targeted and immunotherapies.

Overexpression of the proteins was associated with an adverse prognosis in melanoma patients, according to lead investigator Dr Abdullah Al Emran, researcher in the Melanoma Oncology and Immunology Program at the Centenary Institute

Using in vitro models the team showed that dual targeting with a BET inhibitor (IBET151) and CDK9 inhibitor (CDKI73) synergistically killed melanoma cells  independent of their BRAF or NRAS mutation status.

The dual combination also  markedly inhibited the growth of human melanoma C002M cells in vitro and also in animal models.

“Cell death was associated with mitochondrial depolarisation and caspase dependent apoptosis with cleavage of PARP1 as well as downregulation of anti-apoptotic proteins BCL2, BCLXL and MCL1,” they wrote.

“The inhibitors worked by disrupting separate signalling pathways found within the melanoma cells–those responsible for cell communication and growth and this may explain the effectiveness we saw,” said Dr Al Emran.

“We also found molecular gene signatures suggesting biomarkers of which melanoma patients were most likely to respond to this BET and CDK9 inhibitor treatment,” he added.

“This combination of epigenetic drugs may initially find a role in the treatment of patients with NRAS or BRAF mutations that have failed targeted treatments or immunotherapy with immune checkpoint inhibitors,” the authors suggested

Dr Jessamy Tiffen, Head of the Centenary Institute’s Melanoma Epigenetics Laboratory and senior author on the study said use of combination drug treatments may offer up a new strategic approach for over half of all melanoma patients who do not respond to current therapies.

“We’ve now seen that drugs working in combination are able to produce a synergistic effect when it comes to the killing of melanoma cells. This strategy could lead to higher survival rates for patients and as a result we will be further exploring this exciting avenue of research,” she said.

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