Plenary explores chromosomal instability’s role in cancer treatment
A main focus of cancer treatment for years has been to identify abnormalities in genes that lead to tumorigenesis, but a new plenary session at the American Association for Cancer Research Annual Meeting 2021 focused on another important actor in the process: Chromosomal instability.
Saturday’s Discovery Science Plenary: Mechanisms, Impact, and Exploitation of Cancer Chromosomal Instability – Dedicated to the Memory of Angelika Amonhonored the cell biologist who pioneered research on chromosome imbalance. Amon died in October 2020. Registrants can watch a replay of the plenary anytime until June 21, 2021.
Session moderator Zuzana Storchová, PhD, TU Kaiserslautern, said that chromosomal instability is observed in about 80 percent of human tumors, and mitotic aberrations and chromosomal instability are hallmarks of cancer. The question: Can chromosomal instability be used as a target for novel therapies?
Karlene A. Cimprich, PhD, Stanford University School of Medicine, described her lab’s work on understanding the causes and consequences of replication stress.
DNA damage and replication stress often induce genome instability. Cimprich said there has been intense interest in studying replication stress since it was learned that oncogenes are tumor suppressors and that activated growth factor signaling can lead not only to sustained proliferation but also replication stress, thereby driving genome instability.
Replication stress response helps cells to slow or arrest cycle progression, delay DNA replication, promote and coordinate different forms or repair, and, in the extreme, promote cell death.
“Efforts to understand the fundamental mechanisms of replication stress response by many labs have shown this to be common characteristic of cancer with many causes and consequences,” Cimprich said.
Cancer cells may be critically dependent on the response and have found ways to adapt to and tolerate this stress. This has opened the door to new treatment with ATR inhibitors and other inhibitors targeting the stress response pathway. These are now under active clinical investigation.
Stephen P. Jackson, PhD, Wellcome Trust/Cancer Research, UK Gurdon Institute, discussed how to exploit genome instability for new cancer therapies. DNA is continually subject to a variety of damage, Jackson said, and the body had developed responses to deal with the many DNA lesions.
Jackson’s lab focuses mostly on double strand break DNA damage, which is repaired with two main repair systems: homologous recombination and non-homologous end joining.
BRCA1 and BRCA2, as well as ATM and ATR play key roles in homologous recombination. Jackson explained how understanding these pathways is relevant to cancer and that the loss of these sophisticated regulation systems is toxic to the cells is toxic and has clinical implications.
PARP inhibition offers a great example of harnessing DNA damage repair. Inhibiting PARP leads to accumulation of trapped PARP and single strand breaks. Importantly, if cells are going through the cell cycle during S phase, these breaks and trapped PARP will be processed into double strand breaks that can be repaired, Jackson said.
The repair of these one-ended double-strand breaks requires homologous recombination, which involves BRCA1 and BRCA2, making BRCA1/2-deficient cells particularly sensitive to PARP inhibitors. However, even in situations where BRCA1/2 are mutated or inactivated in cancer cells, not all cancers respond, and some that do acquire resistance.
Scientists are trying to understand the molecular details of drug resistance in these settings.
“Using the concepts of synthetic viability and synthetic lethality we will be able to understand the molecular mechanisms of DNA repair and how they relate to cancer drug sensitivities,” Jackson said. “We will be able to not only identify ways of initially treating cancer but identify resistance mechanisms that could come along with collateral vulnerabilities that could be exploited.”
Samuel F. Bakhoum, MD, PhD, Memorial Sloan Kettering Cancer Center, discussed chromosomal instability and tumor evolution. Tumors with high levels of resistance to multiple lines of therapies often have in common abnormalities in the structure and numbers of chromosomes, Bakhoum said. When chromosomal mis-segregation occurs, where do these chromosomes go?
“These chromosomes can end up in the wrong daughter cell, leading to aneuploidy and abnormalities in copy number of the tumor, or they can lead to formation of micronuclei,” Bakhoum said.
His lab has explored how chromosomal instability promotes tumor progression. The lab developed isogenic cell lines with high or low levels of chromosomal instability through overexpression of either wild-type or inactive kinesin-13 proteins that modulate attachment of microtubules to chromosomes.
In the experiments, all of the cells were either aneuploid and stable or aneuploid and unstable. Cells with high levels of chromosomal instability had higher frequencies of micronuclei. Those with low levels had lower frequencies of micronuclei, Bakhoum said.
This enabled Bakhoum and others to dissect the role of chromosomal instability in tumor progression and metastasis. They transplanted isogenic lines into mice and found a significant correlation between the levels of chromosomal instability in the inoculated cell line and its ability to metastasize and colonize distant organs.
They also found that chromosomal instability also promoted metastasis, in part, through the induction of a chronic inflammatory response that arises from tumor cells.
Bakhoum also reviewed ongoing experiments demonstrating some of the potential therapeutic opportunities provided by a firm mechanistic understanding of how chromosomal instability shapes cancer cell behavior. This knowledge can enable researchers to target these cells by capitalizing on their unique features.
David Pellman, MD, Dana Farber Cancer Institute, discussed mechanisms driving the rapid evolution of cancer genomes. Traditionally, cancer genome evolution was thought of as a classic Darwinian process, but recent work supports new ideas about how highly complex genomes can originate from burst-like mutational processes that extensively alter genomes at once.
Nuclear atypia—the abnormal appearance of cell nuclei – was first described in the late 1880s and has been used since to assigned tumor grade and predict patient prognosis.
“The clinical importance of these abnormalities is very well recognized, but what is missing is a detailed understanding of the causes and consequences of these aberrations—a gap that my group is trying to fill,” Pellman said.
Pellman also touched on continuing work to develop potential therapeutic strategies aimed at chromosomal instability.