Paradigm Shift: There's More to Tumor Drug Resistance Than Just Gene Mutations

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Paradigm Shift: There's More to Tumor Drug Resistance Than Just Gene Mutations
Paradigm Shift: There's More to Tumor Drug Resistance Than Just Gene Mutations

The appearance of new genetic mutations during cancer therapy has long been correlated with drug resistance, treatment failure, and ultimately, relapse. But using single-cell genome sequencing, researchers at the Ontario Cancer Institute and Princess Margaret Cancer Center in Toronto, Canada have shown that gene mutations alone cannot explain drug-resistant cancer.

Tracking individual human colorectal tumor subclone cells that had been xenografted into mice, and sequencing their exomes (the gene-encoding regions of subclone genomes), the team discovered dramatic functional heterogeneity even among genetically identical clones; these included different tumor propagation patterns and different susceptibilities to oxaliplatin, which was reported by the the researchers in Science.1

The findings represent “a major conceptual advance in understanding tumor growth and treatment response,” said senior author John Dick, PhD, a pioneer in cancer stem cell research. “The data show that gene sequencing of tumors to find the spectrum of their mutations is definitely not the whole story when it comes to determining which therapies will be most effective.”

While some cells of a subclone contributed to tumor growth, others quickly became dormant, even though they harbored the same mutations as the more active cells, Dr. Dick's team found—and these dormant cells survived oxaliplatin therapy.

“This is a paradigm shift that shows research also needs to focus on the biological properties of cells,” Dr. Dick said. Treatments that force dormant cells back into growth cycles could make them more sensitive to chemotherapies, he theorizes.

“Targeting the biology and growth properties of cancer cells could expand the repertoire of usable therapeutic agents and provide better outcomes for patients,” he added.

The study is “avante garde in its documentation that types of subcloning can happen against a stability of genetic changes—a clone within a given set of genetic changes can evolve into subpopulations within that clone without changing their genetic background, their mutations,” said Stephen Baylin, MD, Professor of Oncology and Deputy Director of the Cancer Center at the Johns Hopkins University School of Medicine.

Epigenetic factors, such as different DNA-methylation patterns that can silence gene expression, might help explain behavioral heterogeneity among genetically identical subclones, Dr. Baylin postulates.

“If you have got such genetic stability, then it's likely that the other facets of the subclones that emerged could have an epigenetic basis—long-term changes in gene expression,” he told “Things like epigenetic abnormalities could be contributing to the emergence of new subclones with distinct properties.”

The new study “emphasizes those possibilities,” he said. When dormant tumor cells “come out and replenish the tumor,” other studies have shown that they do so with a “different epigenetic state” that appears to contribute to their drug resistance, he noted.

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