Scientists zero in on cellular mechanism fueling drug-resistant cancers

The mystery of how cancers build up resistance mechanisms and evade the treatments that should have destroyed them is a hugely pressing question. Overcoming cancer treatment resistance – a phenomenon that contributes to as much as 90 percent of cancer-related deaths – is among the top missions of 21^st century medical research.

Now, impactful new research from the University of Ottawa Faculty of Medicine could inform future therapeutic approaches targeting cells carrying damaged DNA and aimed at thwarting cancer resistance mechanisms.

Published in Proceedings of the National Academy of Sciences (PNAS), one of the world’s most highly cited scientific journals, Dr. Damien D'Amours and graduate student Laurence Langlois-Lemay have discovered how cells carrying damaged DNA can sidestep cell cycle checkpoints that prevent them from dividing in a damaged state.

This is a highly intriguing finding because these aberrant cells multiply as if they had no damage at all, allowing mutations in DNA to rapidly accumulate in a manner similar to what is seen in treatment-resistant tumors.

Dr. D’Amours, Canada Research Chair in Chromatin Dynamics and Genome Architecture, says the study’s major discovery is highly relevant to cancer treatment because a large number of chemotherapeutic agents are based on targeting and damaging tumor DNA.

“While our study is fundamental in nature, our discoveries provide crucial insights into how cancer cells can resist clinical treatments based on radio/chemotherapy-induced DNA damage,” says Dr. D’Amours, whose team studies the mechanisms that regulate cell division and genome stability in eukaryotes -- an extraordinary range of organisms, including human beings, that descended from a common ancestor that lived roughly two billion years ago.

DNA damage & cell proliferation

The new findings from Dr. D’Amours’ lab advances our understanding of centrosomes – miniscule organelle structures within cells tasked with various essential functions including responsibility for chromosome division.

The study found that centrosomes are in fact playing a key and unexpected role as signaling hubs that help cells decide if they can proliferate in the presence of DNA damage that can’t be repaired.

The research further indicates that drug-based inhibition of Polo-like kinase 1 (PLK1) – an enzyme that plays a big part in cell cycle regulation – represents a promising strategy to prevent adaptation to therapy-induced DNA damage and drug resistance to cancer therapies.

Dr. D’Amours explains they found that recruitment of the PLK enzyme to centrosomes is an essential step in promoting adaptation toward severe DNA damage – a process that can lead to proliferation of abnormal cells carrying DNA lesions in cancer patients.

“Cell proliferation in the presence of DNA lesions is arguably the most effective way to generate cancers in humans. Ramped-up recruitment of PLK1 at centrosomes is therefore expected to promote adaptation to DNA damage, leading to aberrant cell proliferation and its pro-oncogenic effects in patients,” he says.

Forging hard-won discoveries

The ambitious study’s discoveries took years of methodical and creative scientific work.

It began in 2017 when Dr. D’Amours was recruited to the University of Ottawa to work on deciphering the molecular pathways responsible for the maintenance of genome integrity in living cells. His lab moved from Université de Montréal to the uOttawa Faculty of Medicine that year.

He says Langlois-Lemay, then an MSc student in his lab, used a “systems biology approach” to model the adaptation response in budding yeast, a model organism with a well-studied genome used by scientists to study a wide range of biological processes and perform complex genetic modifications not possible in human cells.

Employing the cutting-edge technological facilities at uOttawa’s Institute of Systems Biology (OISB), she found that an evolutionarily conserved centrosome component was necessary for the yeast PLK to associate with centrosomes and promote the adaptation response to DNA damage. She started a PhD program to explore these questions, chipping away at the study now published in PNAS as a member of Dr. D’Amours’ lab. She will be defending her thesis this summer.

“As a supervisor, I consider this a real ‘success story’ for both Laurence and uOttawa,” says Dr. D’Amours, Professor in the uOttawa Faculty of Medicine’s Department of Cellular and Molecular Medicine.

Validating findings & advancing knowledge

Armed with new knowledge about the mechanisms underlying cellular adaption to DNA damage, scientists could eventually design new strategies to better understand resistance and prompt bench-to-bedside translation from the laboratory into the clinic.

That’s precisely the kind of approach that Dr. D’Amours and his team will focus on next.

He says their next step is to validate these discoveries in a clinical context, particularly how chemical inhibition of human PLK1 may suppress adaptation to DNA damage and subsequently enhance the effectiveness of radio/chemotherapy in cancer patients.

The study was bolstered by financial support from a CIHR Foundation Grant. It could not have been achieved without access to cutting-edge technological facilities at the uOttawa Faculty of Medicine and uOttawa’s Institute of Systems Biology. Langlois-Lemay’s thesis advisory committee also provided valuable insights, according to Dr. D’Amours.