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Review
. 2022 Aug 25:13:967633.
doi: 10.3389/fphar.2022.967633. eCollection 2022.

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

Nannan Wang  1 , Yan Yang  2 , Dongdong Jin  1   3 , Zhenan Zhang  1 , Ke Shen  1 , Jing Yang  1 , Huanhuan Chen  1 , Xinyue Zhao  1 , Li Yang  1   3 , Huaiwu Lu  4
Affiliations
Review

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

Nannan Wang et al. Front Pharmacol. .

Abstract

Breast cancer and gynecological tumors seriously endanger women's physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

Keywords: ATR/CHK1/WEE1 pathway; PARP inhibitor; PARP inhibitor resistance; breast cancer; combination therapy; gynecological cancer; targeted drugs.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The mechanism of action of PARP inhibitors for “synthetically lethality.”
FIGURE 2
FIGURE 2
Partial mechanisms of PARP inhibitor resistance in cancer. (A) Restoration of replication fork stability leads to PARP inhibitor resistance. When EZH2 or MLL3/4-PTIP is deficient, MUS81 and MRE11 recruitment fails, the replication fork is less attacked, and the replication fork is stable. (B) Decreased PARP1 trapping contributes to the development of PARP inhibitor resistance. PARP inhibitors reduce the catalytic activity of PARP1, so that PARP remains bound to DNA and cannot undergo subsequent repair. PARP1 mutations reduce PARP capture. (C) Increased drug efflux mediated by ABCB1 overexpression leads to a decrease in effective concentration in cancer cells and increased resistance to PARPi.
FIGURE 3
FIGURE 3
Partial mechanisms of PARP inhibitor resistance in cancer. (A) PARG deletion leads to PARPI resistance. (B) Loss of SLFN11 enhances DSB repair capacity, ultimately leading to PARPi resistance. (C) The ATR/CHK/WEE1 signaling pathway arrests the cell cycle to reduce replication stress and promote DSB repair. (D) HR-deficient cells rely on MMEJ for DSB repair, which is mediated by POLθ. Inhibition of POLθ in HR-deficient cells results in cell death.
FIGURE 4
FIGURE 4
Mechanism of HR-dependent pathway leading to PARPi resistance.
FIGURE 5
FIGURE 5
Combination treatment options for ovarian cancer resistant to PARPi. Figures have been created with BioRender.com.
See this image and copyright information in PMC

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