Investigation of PARP inhibitor resistance through the analysis of serially collected circulating tumor DNA (ctDNA) in ovarian cancer patients (027)

Kim, Yoo-Na; Shim, Yeeun; Lee, Jung‐Yun; Lee, Seung Tae; Seo, Jiyeon; Lee, Yong Jae; Shin, Saeam; Kim, Sang Wun; Choi, Jong Rak; Kim, Sung Hoon

doi:10.1016/s0090-8258(22)01245-8

Cited by 2 publications

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“…Based on the ctDNA mutation profiles from pre- and post-treatment matched samples, mutations specifically present in post-treatment samples (i.e., not present in pre-treatment samples) were identified in each patient ( 31 ) and used to identify resistance mechanisms. As performed in our previous approach ( 30 ), individual genes in the TMB500 panel were individually reviewed to determine their implication in PARPi resistance.…”

Section: Methodsmentioning

confidence: 99%

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

Kim,

Joung

et al. 2024

Front. Oncol.

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ObjectiveEffective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with BRCA mutation or HR deficiencies, accurately identifying de novo or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer.MethodsOvarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure (“pre-PARPi”) and/or after progression on PARPi (“post-PARPi”) were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value.ResultsIn total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0–90) overall, 10 (0–190) in pre-PARPi samples (n = 34), and 25 (1–170) in post-PARPi samples (n = 19). Among patients with BRCA mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (P = 0.029). No difference was found in PFS with respect to the genomic scar score (P = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients.ConclusionRAD51 is a potential functional IHC biomarker of de novo and acquired PARPi resistance in BRCA-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.

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Section: Methodsmentioning

confidence: 99%

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

Kim,

Joung

et al. 2024

Front. Oncol.

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“…Although PARPi has demonstrated excellent antitumor efficacy in clinical trials, its drug resistance has become a challenge that hinders its widespread use. The complicated resistance mechanisms of PARPi comprise drug efflux, BRCA1/2 reverse mutation, HR repair restoration, and replication fork protection restoration 43–45 . For instance, the distinctive alterations in various overlapped repair pathways contribute to a multifaced resistance of PARPi 46–48 .…”

Section: Functional Connection Of Sl In Individual Cancer Cellsmentioning

confidence: 99%

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

Ge,

Luo,

et al. 2024

MedComm – Oncology

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Synthetic lethality (SL), a genetic concept, has revolutionized the development of antitumor therapies by providing avenues to target previously “undruggable” targets with enhanced specificity for tumor cells over normal tissue. The principles of SL have expanded beyond genetic definitions to encompass biological functions, including genome stability, cell cycle regulation, cell death mechanisms, cellular metabolism, cell–cell interactions, and the tumor microenvironment (TME). Tumor cells with inactivated survival pathways are sensitive to therapeutic inhibition of compensatory mechanisms, while normal cells remain unaffected. Exploiting SL based on functional contexts has the potential to significantly improve cancer patient survival by reducing resistance to targeted therapies and enhancing antitumor efficacy when combined with other treatment modalities. This review explores the underlying mechanisms of synthetic lethality interactions (SLI) characterized by biological functions in individual cancer cells and the TME. We also provide a comprehensive summary of strategies for leveraging the dynamic nature of SLI to overcome therapeutic resistance. Additionally, we discuss various approaches and models for screening and designing potent SL agents tailored to the specific needs of cancer patients, as well as strategies for combining SL drugs in tumor treatment. This review offers valuable insights into harnessing SL as a promising avenue for precision cancer therapy.

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Investigation of PARP inhibitor resistance through the analysis of serially collected circulating tumor DNA (ctDNA) in ovarian cancer patients (027)

Cited by 2 publications

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RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

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