Understanding Cancer Chromosomal Instability: Highlights from the AACR2021 Discovery Science Plenary Session

The ongoing COVID-19 pandemic has forced the annual AACR conference to go virtual for the second year in a row. Below, we present the highlights of the Discovery Science Plenary session that focused on “Mechanisms, Impact, and Exploitation of Cancer Chromosomal Instability”, in honor of the late Dr. Angelika Amon.

Mitosis occurs in normal cells, as well as in cancer cells; however, most cancers undergo abnormal cell division that results in chromosomal errors and mutations. This genomic instability is one of the hallmarks of cancer. These constant errors in mitosis produce heterogeneous populations and give way to mutations that allow cells to metastasize and drive resistance to treatment. How genomic instability emerges is not fully understood, but increasing our understanding of this process could lead to novel therapeutics.

Micronuclei and DNA Damage Lead to Fast Changes in Cancer Genomes

Dr. David Pellman from the Dana-Farber Cancer Institute presented data on how normal genomes transform into cancer genomes. He focused on whole-genome duplication, chromothripsis, breakage-fusion-bridge cycle, which are major processes known to drive rapid genomes changes.

Whole-genome duplication and breakage-fusion-bridge cycles lead to incorrect chromosome segregation and the formation of micronuclei. These micronuclei suffer at least three DNA damage steps that contribute to rapid genomic changes.

1) Micronuclei have a dysfunctional nuclear envelope that, when ruptured, triggers DNA damage,

2) During the next round of mitosis, these mutated chromosomes undergo massive errors in DNA replication

3) These chromosomes can be furthered modified by a process known as chromothripsis or chromosome shredding.

All of these can result in a cancer-driving mutation, as well as rapid changes in cancer cells. However, recent studies have shown that whole-genome duplication creates specific dependencies in cells, which could be exploited for therapeutic purposes.

Dr. Pellman concluded his talk by giving a warning about the on-target toxicity of CRISPR-Cas9 therapeutics. This technique can lead to chromosome breakage and result in chromothripsis. An important consideration to keep in mind as this technology becomes more widespread.

Cancer Exploits DNA Sensing Signals to Induce Metastasis and Suppress Immune Activation

Dr. Samuel Bakhoum, a physician-scientist at Memorial Sloan Kettering Cancer Center and co-founder of Volastra Therapeutics, talked about aneuploidy, where cells can have an abnormal number of chromosomes but still be stable. The presence of chromosome instability (CIN) and the resulting formation of micronuclei are predictors and drivers of metastasis.

He discovered that when micronuclei rupture, they expose their double-stranded DNA (dsDNA) to the cytoplasm, which results in activation of the innate immune response and inflammatory response. The presence of dsDNA in the cytoplasm is a sign of viral infection, and in normal cells, activation of the inflammatory pathways leads to cell death or recruitment of immune cells to eliminate the infected cells. Surprisingly, in cancer cells, this activation of inflammatory signals led to an increase in metastasis.

To accomplish this, cancer cells desensitize their internal dsDNA-sensing pathway, and they suppress the activation of macrophages in the tumor microenvironment. They accomplish this by altering the ER-stress/Unfolded Protein Response (UPR) pathway and inducing cGaMP protein. Using samples from ovarian patients, Dr. Bakhoum determined that CIN and micronuclei are associated with reduced IFN signaling and activation of the UPR pathway.

Additionally, immune cells in the tumor microenvironment also showed a reduction in IFN signaling. Based on these observations, Dr. Bakhoum’s group targeted a protein known as STING, which plays a crucial role in dsDNA sensing. Inhibiting or depleting this protein suppressed metastasis. Targeting other parts of this pathway could be a viable therapeutic approach to prevent metastasis and activate immune cells to combat cancer.

Cancer Cells Inadvertently Become Vulnerable after Gaining Resistance to PARP Inhibitors

Dr. Stephen P. Jackson, a professor at the University of Cambridge and founder of KuDOS Pharmaceuticals, talked about the benefits of targeting DNA damage response (DDR) pathways in cancer. He focused on drugs that target PARP, a protein involved in the repair of single-strand DNA breaks. By inhibiting the active site, it traps PARP in the DNA and leads to the accumulation of double-strand DNA breaks. To repair the double-strand break, cells rely on two main pathways: 1) homologous recombination (HR) and 2) non-homologous end-joining (NHEJ).

Breast and other types of cancers have mutations in genes necessary for DNA repair, such as the BRCA1/2 genes, which are essential for HR repair. Consequently, cancer cells with these mutations are inefficient at repairing the damage by increasing and preventing repair of DNA damage via inhibition of PARP results in cells dying. However, cancers develop resistance to PARP inhibitors by eliminating proteins that promote NHEJ and counter HR.

Once NHEJ involved proteins are missing, HR can occur, even without the BRCA genes, which leads to cancer cell survival. However, the cells become more vulnerable to other DNA agents since they suppressed their two DNA repair mechanisms. These observations open the possibility of guiding cells towards becoming more vulnerable and developing new therapies that exploit these vulnerabilities.

Understanding Replication Stress Machinery Could Lead to the Discovery of New Therapies

Dr. Karlene Cimprich, a Professor at Stanford University, presented about genomic instability, a hallmark of cancer, that can serve as a driver for other hallmarks, and some of the alternative pathways that cancer cells activate to survive. Her talk focused on replication stress caused by DNA lesions, secondary structures, and others. Cancer cells under constant replication stress and rely on replication stress response to survive. Several companies are targeting members of the replication stress response for therapeutics.

Additionally, she discovered that to avoid replication stress damage, cancer cells activate alternative DNA replication machinery. Understanding the activation of these pathways could open new therapeutic avenues.

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Author

Daniel Ojeda