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Genetic contribution to late-stage cancer treatment resistance identified

New research has identified some factors that may lead to some skin cancers no longer responding to treatment.

Published in Cancer Discovery, the study was an in-depth analysis of 14 patients who died from incurable melanoma. Scientists took 573 samples from 387 tumours from patients with advanced melanoma. Research autopsies were carried out soon after death at University College London Hospitals and Guys and St Thomas’ Mortuary, with samples analyzed at the Francis Crick Institute and University College London.

All of the patients in the study had been treated with immune checkpoint inhibitor (ICI) therapies, which help the immune system recognize and attack cancer cells. In all 14 patients, ICI drugs had stopped working by the time of their deaths.

To better understand why the treatment had stopped being effective, the researchers examined the genetic code of individual cells within the tumour samples, looking for patterns in how the code changed when the tumours spread and resisted treatment.

They found that 11 out of the 14 patients in the study had lost functioning genes that enable ICI drugs to help the immune system recognize and attack the cancer. They write that this loss occurs because the cancer can either make multiple copies of defective versions of the genes or use circular rings of DNA from outside the chromosome (called extrachromosomal DNA) to override normal copies of the genes.

In a press release, study author Dr. Samra Turajlic said: “Treatment options for patients whose melanoma that returned or spread have improved dramatically in the last decade. But sadly, almost half of melanoma patients still lose their lives to their cancer.”

Dr. Turajlic is a Consultant Medical Oncologist at the Melanoma Unit at the Royal Marsden and Research Group Leader at the Francis Crick Institute in London.

“To understand why existing treatments sometimes fail, we need to know what happens in the final stages of their cancer,” she said. “It’s difficult, but the only practical way to do this is to analyze tumour samples after people have died from their cancer.”

“We found that melanoma can profoundly alter its genome to hide from the immune system and spread around the body. These profound changes are highly complex, but we’re hopeful that we can now find ways to target them in the clinic.”


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