Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers

Sun, Chang; Zhang, Fan; Tang, Xiang; Chen, Qianming; Pandita, Tej K.; Huang, Yuping; Hu, Mickey C.T.; Yang, Qin

doi:10.18632/oncotarget.1952

Cited by 32 publications

(43 citation statements)

References 42 publications

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“…In these cells, moreover, all the exons of BRCA1 , BRCA2 , ATM and TP53 showed no differences (Table ). PTEN regulates the Akt‐mTOR‐ribosomal protein S6 signaling axis and phosphorylation of S6 has been reported to participate in PARPi resistance . However, the levels of the components in this signaling axis, including Akt, p‐S473‐Akt and S6, p‐S235/236‐S6 or p‐S240/244‐S6, showed no differences in the resistant and parental cells (Figure F).…”

Section: Resultsmentioning

confidence: 95%

“…PTEN regulates the Akt-mTOR-ribosomal protein S6 signaling axis and phosphorylation of S6 has been reported to participate in PARPi resistance. 22 However, the levels of the components in this signaling axis, including Akt, p-S473-Akt and S6, p-S235/236-S6 or p-S240/ 244-S6, showed no differences in the resistant and parental cells ( Figure 2F). The result indicates that PARPi resistance is independent of the PTEN-Akt-mTOR-S6 signaling axis in these variants.…”

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confidence: 94%

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Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

et al. 2018

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With increasing uses of poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)‐deficient background is poorly understood. We generated 3 PARPi‐resistant PTEN‐deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46‐71.78‐fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi‐treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross‐resistance profiles to 13 non‐PARPi anticancer drugs. All were resistant to Ara‐C (6‐8‐fold) but showed differential resistance to 5‐fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara‐C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross‐resistance profile to non‐PARPi drugs in different PARPi‐resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara‐C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

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Section: Resultsmentioning

confidence: 95%

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confidence: 94%

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

et al. 2018

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“…It has been recently reported that inhibition of S6RP phosphorylation by mTOR inhibitor rapamycin restores the sensitivity to PARP inhibitor Olaparib [28]. We next examined if reduced S6RP phosphorylation as a result of PI3K inhibition by BKM120 may sensitize OVCA433 cells to PARP inhibition by Olaparib (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown recently that phosphorylation of S6RP confers PARP inhibitor resistance in BRCA-deficient cancers [28]. In line with this, the current study with wild-type PIK3CA ovarian cancer cells and our recent study with PIK3CA mutant ovarian cancer cells [20] revealed that irrespective of BRCA or PIK3CA mutational status, ovarian cancer cells with concomitant downregulation of phosphorylated S6RP following PI3K inhibitor BKM120 or mTOR inhibitor RAD001 treatment exhibited impaired DNA damage response and compromised homologous recombination repair, and were thus responsive to PARP inhibition.…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes

Wang

Zhang

et al. 2016

Gynecologic Oncology

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Objective Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. Methods We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and /or a PARP inhibitor Olaparib. The effect of BKM120 as a single-agent or in combination with Olaparib was evaluated by Cell Count Kit (CCK8) assay, immunoblotting, comet assay, flow cytometry and immunofluorescence staining assay. The combination indexes for synergistic effect on cell viability were calculated with the Chou-Talalay method. Ex vivo cultured ovarian cancer tissues from patients were analyzed by histological and immunohistochemical analyses. Results Combined inhibition of PI3K and PARP effectively synergized to block the growth of three wild-type PIK3CA ovarian cancer cell lines and explants of a primary ovarian tumor specimen. Mechanistically, dual blockade of PI3K and PARP in these ovarian cancer cell lines resulted in substantially attenuated PI3K/AKT/mTOR signaling, impaired DNA damage response and deficient homologous recombination repair, with remarkable BRCA downregulation. Conclusions The combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib may be effective in ovarian cancers with a broader spectrum of cancer-associated genetic alterations but not limited to those with mutant PIK3CA or BRCA genes. BRCA downregulation may be a potential biomarker for the effective response to the proposed combination treatment.

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“…The extrapolation of these findings to the scenario in human cancer suggests that the combination of adaptation inhibition with genotoxic drugs may give the desired effect of only causing cytotoxicity in the repair-defective tumor cells and not in the repair-proficient healthy tissue. In support of this notion, it has been demonstrated that BRCA1 -/breast cancer cells are hypersensitized to PARP inhibitors (PARPi) in the presence of rapamycin (Osoegawa et al, 2017;Sun et al, 2014), although the role of checkpoint adaptation was not assessed in these studies. Furthermore, inhibition of PLK1 also leads to PARPi hypersensitization in BRCA1 -/cells (Li et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

Bender¹,

Vydzhak²,

Klermund³

et al. 2018

Preprint

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Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ repair-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.

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Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers

Cited by 32 publications

References 42 publications

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes

Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

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