What Underlies PARP Inhibitor Resistance in Ovarian Cancer?


New research examines the mechanisms underlying why most patients with high-grade serous ovarian cancer develop resistance to PARP inhibitors.

New research presented at the 12th Biennial Ovarian Cancer Research Symposium held September 13–15 in Seattle advances toward a better understanding of the mechanisms underlying why most patients with high-grade serous ovarian cancer (HGSOC) develop resistance to poly (ADP-ribose) polymerase (PARP) inhibitors, with the aim to eventually find ways to identify patients most likely to overcome resistance and respond to PARP inhibitors.

Investigators from the lab of Alan D. D’Andrea, MD, at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School in Boston, presented the findings of several studies that examine specific aspects of a few of these mechanisms.

“There are many challenges to studying chemoresistance, and this work addresses a couple of them,” said Charles “Chip” Landen, MD, associate professor of gynecologic oncology and co-leader of the cancer therapeutics program at the University of Virginia Cancer Center in Charlottesville, who was commenting on the studies. “One of the primary problems is tumor heterogeneity.”

“Since we can get most patients into a remission through a combination of surgery and chemotherapy, yet most patients still recur, there must be some small population of tumor cells that is resistant to therapy and causes recurrence,” said Landen.

As such, a better understanding of the functional heterogeneity of different PARP inhibitor resistance mechanisms is one aspect of chemoresistance that could lead to the development of biomarkers for acquired PARP inhibitor resistance. This was discussed in a study by lead author Anniina Färkkilä, MD, PhD, of Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, entitled, “Functional Heterogeneity of Acquired PARP Inhibitor Resistance in BRCA1-Deficient Cells.”

In the study, Färkkilä and colleagues developed an experimental model to study the mechanisms of PARP inhibitor resistance, in which they generated P53- and BRCA1-deficient cells that were made resistant to PARP inhibitors, and demonstrated significant functional heterogeneity in DNA repair dynamics in subclones from these cells. “We observed significant heterogeneity of resistance mechanisms inside the pool of P53- and BRCA1-deficient, PARP inhibitor–resistant cells,” said Färkkilä. “Also, the single cell clones from this pool showed simultaneous activation of multiple distinct resistance mechanisms.”

“By studying single cells instead of groups of cells, they may be able to find differences in these individual cells that sheds light on tumor heterogeneity,” said Landen.

The research points to the possibility that several distinct resistance mechanisms potentially linked to DNA damage response regulation underly acquired PARP inhibitor resistance.

“PARP inhibitor resistance seems to develop via multiple mechanisms, and after resistance has emerged the tumor will be highly heterogeneous,” noted Färkkilä.

Clinical translation of this could potentially lead to therapeutics that target resistance mechanisms with new DNA damage repair. “Early combination therapies might prevent the emergence of PARP inhibitor resistance,” she added.

Related Videos
Brian Slomovitz, MD, MS, FACOG discusses the use of new antibody drug conjugates for treating patients with various gynecologic cancers.
Developing novel regimens may continue to improve survival outcomes of patients with advanced cervical cancer following the FDA approval of pembrolizumab and chemoradiation, says Jyoti S. Mayadev, MD.
Treatment with pembrolizumab plus chemoradiation appears to be well tolerated with no detriment to quality of life among those with advanced cervical cancer.
Jyoti S. Mayadev, MD, says that pembrolizumab in combination with chemoradiation will be seamlessly incorporated into her institution’s treatment of those with FIGO 2014 stage III to IVA cervical cancer following the regimen’s FDA approval.
Domenica Lorusso, MD, PhD, says that paying attention to the quality of chemoradiotherapy is imperative to feeling confident about the potential addition of pembrolizumab for locally advanced cervical cancer.
Guidelines from the Society of Gynecologic Oncology may help with managing the ongoing chemotherapy shortage in the treatment of patients with gynecologic cancers, according to Brian Slomovitz, MD, MS, FACOG.
Interim data reveal favorable responses in patients with low-grade serous ovarian cancer treated with avutometinib plus defactinib, according to Susana N. Banerjee, MD.
Brian Slomovitz, MD, MS, FACOG, notes that sometimes there is a need to substitute cisplatin for carboplatin, and vice versa, to best manage gynecologic cancers during the chemotherapy shortage.
Findings from the phase 3 MIRASOL trial support mirvetuximab soravtansine as a standard treatment option for platinum-resistant ovarian cancer, according to Ritu Salani, MD.
Trastuzumab deruxtecan appears to elicit ‘impressive’ responses among patients with HER2-positive gynecologic cancers regardless of immunohistochemistry in the phase 2 DESTINY-PanTumor02 trial.
Related Content