Monash researcher sheds light on therapy resistance in cancer



Luciano Martelotto

Collaborative research including Monash University has uncovered the principles behind why some tumours may become resistant to targeted therapies, paving the way for new and more effective cancer treatments.

Published last week in Nature Medicine, a team of researchers including Dr Luciano Martelotto from the School of Clinical Sciences at Monash Health (SCS) in collaboration with Dr Piro Lito’s laboratory at the Memorial Sloan Kettering Cancer Center, New York, have found a mechanism that explains why and how resistance to therapy occurs in certain cancers, and identified types of therapies to prevent this process from occurring.

Lead author Dr Martelotto said that until now, the way that tumours respond and become resistant to therapies has been poorly understood.

“In our study, we generated models of melanoma and lung patients’ tumour cells and used modern DNA sequencing technologies to examine the genetic information of many individual malignant cells to better understand how tumour DNA changes in response to therapy,” Dr Martelotto said.

“This is important because it helps explain how these changes in the genetic material help the cancer escape the effects of the treatment.”

“For the first time, we’ve demonstrated that solid tumours like melanoma and lung cancers can grow back shortly after therapy, but when they do they are made of genetically diverse sub-groups of malignant cells—and, scarily enough, all of these are resistant to treatment. This genetic diversity is what allows the cancers to adapt to the treatment and resist it.”

The research team used their results to create a hypothetical model of resistance (called a fitness threshold model), enabling them to understand how the resistance mechanism works.

“We knew that drugs targeting different parts of the same cellular pathway have distinct mechanisms and, as a consequence, we proposed that they should also exert different selective pressures on cancer cells,” Dr Martelotto said.

The research team’s fitness threshold model links the effect of a given drug with the selection of resistance-causing alterations in DNA, resulting in significant implications for the treatment of cancer patients.

“We’ve now shown that sequentially treating tumours with drugs that neutralise different parts of the same pathway is ineffective; however, when the drugs are combined and administered in anintermittent regime, the treatment becomes highly effective and without apparent toxicity,” Dr Martelotto said.

Dr Martelotto said that these findings are important for oncologists and patients because they show that the way that drugs are administered during therapy can have a critical impact on the outcome of the response to treatment.

“In our work, we showed that intermittent administration enables simultaneous delivery of multiple targeted therapies while maintaining lower toxicity, and our fitness threshold model explains how other resistance-causing alterations may develop during targeted therapy,” Dr Martelotto said.

This important finding sheds light into the development of newtherapeutic designs to more effectively treat patients.