Dr Hatem Soliman Explains How the DNA Damage Repair Pathway Affects Cancer Progression

Hatem Soliman, MD, medical director of the Clinical Trials Office, Moffitt Cancer Center, discusses effects of the DNA damage repair pathway on cancer progression, as well as how various inhibitors address DNA mutation and damage in metastatic breast cancer (MBC).

Transcript

How does the DNA damage repair pathway affect cancer progression, and how do PARP, PI3K, and CDK4/6 inhibitors address DNA mutation and damage in MBC?

Cancer fundamentally is a disease of the genome-acquiring mutations over time that transform the cells from normal cells that respond appropriately to growth signals and also to program death signals, when appropriate, to cells that become immortalized and grow without restriction or regard to the host.

DNA damage that is acquired over time can lead to the acquisition of additional properties, such as increased signaling of mitogenic growth factors or other secondary messengers that lead to an unchecked ability of those cells to divide and ignore growth restriction or growth inhibition signals that would ordinarily keep normal tissues from dividing in an uncontrolled manner.

The DNA damage repair pathway is a highly conserved and very important part of our normal biology, which has a lot of built-in redundancies in order to try to prevent that scenario from occurring more frequently. That's one of the key reasons why more people aren't diagnosed with cancers than we currently see—because these pathways are constantly on guard for acquired mutations in the DNA that can occur daily due to exposure to everyday environmental insults, such as background radiation, UV [ultraviolet], carcinogens in our food and in the air, smoking, alcohol, other lifestyle issues that can lead to DNA damage over time. Without these pathways present, these mutations can accumulate and lead to the transformation of normal cells into malignant cells that eventually are diagnosed as tumors down the road.

I think it's very important to realize this is a fundamental biologic milestone that transformed cells have to overcome—that acquiring these traits of mutated pathways is a direct result of dysfunctional DNA repair that has allowed these errors to continue and propagate going forward within the malignant tissue.

Now, some of the ways that various pathways can factor into how DNA damage repair capacity is altered in cancer cells is very important to appreciate. Furthermore, how can we exploit these types of DNA damage repair deficiencies as a sort of Achilles heel to try to treat cancer and lead to a benefit for the patient in controlling their disease?

One of the classic ways of doing this is by using a class of drugs called PARP [poly (ADP-ribose) polymerase] inhibitors. PARP is an enzyme, which is key in the repair of a single strand of breaks within the DNA. This enzyme, in particular, is heavily used by cells that have defect in the BRCA1 and BRCA2 genes. These are other genes that have been discovered to lead or confer to a higher risk of inherited breast cancer in patients who have germline mutations in these important DNA repair genes. When a patient has a mutation in BRCA1 or BRCA2 and develops a cancer, their cells become heavily dependent on PARP in order to try to maintain the integrity of DNA and prevent catastrophe occurring at some point in the division of those cells due to too much damage to the DNA.

When you use a PARP inhibitor in that scenario, you exploit a phenomenon called synthetic lethality, by which, by blocking part, you also then do a 1-2 punch basically on those cells and cause them to succumb to catastrophic DNA damage, because now you've blocked 2 methods of DNA repair—BRCA1 or BRCA2 through the mutation they inherited and also PARP inhibition by the drug that you're giving, such as olaparib or talazoparib. This is an important fundamental property of tumors that are present in patients with inherited mutations in BRCA1 and BRCA2.

Now with PIK3CA, this is an important signaling and growth pathway, which is involved in a number of different cancers. This pathway can be mutated in between 30% to 40% of women with estrogen receptor–positive HER2-negative breast cancer and is the basis of the approval for a specific PIK3CA alpha inhibitor known as alpelisib, based on the results of the SOLAR-1 trial, which treated women that did have a detectable PIK3CA mutation and were estrogen receptor–positive and HER2-negative. This drug is given in combination with fulvestrant, a selective estrogen receptor degrader.

What we've seen in research is that this pathway is activated in this proportion of patients. By targeting them with alpelisib, we can effectively shut down growth in these cells and cause regression in tumors [in] patients that do have this activating mutation. Interestingly, by inhibiting PIK3CA, this also can lead to a decline in the ability of the cells to repair their DNA, in a way almost recapitulating a kind of BRCA-like phenomenon, so that by blocking PIK3CA, you could potentially render them more sensitive to DNA damaging agents—such as PARP inhibitors—down the road when they also have a BRCA1 or BRCA2 germline mutation. That interaction is something that needs to be explored further in order to figure out what's the optimal sequence of agents that we can use, in order to try to set the tumors up to take a fall harder with the PARP inhibitors after they've been treated with drugs like alpelisib.

Finally, with CDK4/6 inhibitors, these drugs primarily work by inhibiting the division of cells. There're a number of checkpoints within the cell division cycle that serve as a way to prevent cells from growing in an unchecked fashion. CDK4 and 6 are 2 of these key proteins, which are dysregulated in the cell cycle of women, particularly with estrogen receptor–positive HER2-negative breast cancer. That blockade of CDK4 and 6 with drugs such as palbociclib, abemaciclib, and ribociclib can be highly effective in this population of patients to suppress growth for an extended period of time and dramatically increase the progression-free survival.

Now, how this class of drugs interact with DNA damage repair pathways is still a subject of research and much interest. Generally speaking, most of these patients, even when they [have] BRCA1 or BRCA2 mutated tumors that are estrogen receptor–positive, the priority will be to try to treat women with CDK4/6 inhibitors in the first-line setting, even if we know that they have an inherited mutation in BRCA1 or BRCA2.