Targeting autophagy reverses de novo resistance in homologous recombination repair proficient breast cancers to PARP inhibition

Bellare, Ganesh Pai; Saha, Bhaskar; Patro, Birija Sankar

doi:10.1038/s41416-020-01238-0

Cited by 28 publications

(26 citation statements)

References 52 publications

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“…This is the basis for the synthetic lethality of PARP inhibitors (PARPis) in cancers with HR deficiency due to mutations in BRCA1/2 or other HR genes 5 , allowing these cancer cells to be selectively targeted while sparing normal cells that have intact DNA repair systems 6 . Most recently, targeting autophagy was also demonstrated to enhance the therapeutic efficacy of PARP inhibitor in HR proficient breast cancer cells 7 . Several PARPis have been approved for the therapy of HR-deficient tumors 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Zhang

Peng

et al. 2021

Cell Death Dis

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PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of “synthetic lethality”. However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.

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Section: Introductionmentioning

confidence: 99%

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Zhang

Peng

et al. 2021

Cell Death Dis

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“…Furthermore, many genomic biomarkers associated with homologous recombination deficiency confer benefits upon patients administered PARP inhibitors and long-term clinical practice (long-term PARP inhibitor therapy, other therapeutics, palliative care, etc.) ( Pai Bellare et al, 2021 ; Setton et al, 2021 ; Verma et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Protumorigenic Role of Elevated Levels of DNA Polymerase Epsilon Predicts an Immune-Suppressive Microenvironment in Clear Cell Renal Cell Carcinoma

Tang

et al. 2021

Front. Genet.

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Increasing evidence indicates that DNA polymerase epsilon (POLE), which mediates DNA damage repair, is significantly associated with tumor prognosis. This study aimed to analyze POLE expression in tumor samples and its prognostic value for patients with clear cell renal cell carcinoma (ccRCC). We found significantly elevated POLE expression in ccRCC tissues compared with normal tissues of multiple independent cohorts. The POLE expression levels of 523 patients with ccRCC (The Cancer Genome Atlas RNA-seq data) and 179 patients with ccRCC with immunohistochemical data (Fudan University Shanghai Cancer Center) were analyzed to investigate the prognostic implications of POLE expression. Cox regression analyses were implemented to explore the effect of POLE expression on the prognosis of pan-cancer. These findings revealed that elevated POLE expression levels significantly correlated with shorter overall survival (p < 0.001, n = 701) of patients with ccRCC. These data indicate that POLE expression may serve as a prognostic biomarker for cancers. Although POLE mutations were not significantly associated with survival benefits conferred upon patients with ccRCC, a CD4+ T cell-regulated immune microenvironment was significantly activated. Moreover, we found that POLE expression in cancers significantly correlated with an immunosuppressive tumor microenvironment, higher intratumoral heterogeneity, and expression of immune checkpoint genes PDCD1, CTLA4, and CD86, possibly mediated via the JAK/STAT and Notch signaling pathways. In conclusion, the present study is the first to our knowledge to indicate that elevated POLE expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that POLE can serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.

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“…Several conjugates of ADP and morpholino nucleosides target PARP1/2/3 with high specificity [ 89 ], while ABT-888 showed high specificity toward PARP2 [ 90 ]. A different approach to reverse PARP inhibitors resistance has been proposed through targeting autophagy, and the enzymes controlling autophagy in HR repair proficient breast cancers [ 91 ]. Topoisomerase 1 inhibitors have been shown to be effective in cancer therapy of HR-deficient, Schlafen 11-positive cells in association with Olaparib, for the treatment of BRCA1 -, BRCA2 -, and PALB2 -deficient cells [ 92 ].…”

Section: Cancer Proliferation Metastasis Angiogenesis: the Role Of Adp-ribosylating Enzymes According To A Deregulated Expression Or Use mentioning

confidence: 99%

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri

Misawa

Masutani

2021

IJMS

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Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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Targeting autophagy reverses de novo resistance in homologous recombination repair proficient breast cancers to PARP inhibition

Cited by 28 publications

References 52 publications

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Protumorigenic Role of Elevated Levels of DNA Polymerase Epsilon Predicts an Immune-Suppressive Microenvironment in Clear Cell Renal Cell Carcinoma

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

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