scholarly journals Loss of Nuclear DNA ligase III Can Revert PARP Inhibitor Resistance in BRCA1-deficient Cells by Increasing DNA Replication Stress

2021 ◽  
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Chromosomal Abnormalities ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Replication Forks ◽  
Genetic Screens ◽  
Dna Replication Stress ◽  
Inhibitor Resistance

SUMMARYInhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1, identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 is required for PARPi-induced fork acceleration in BRCA1-deficient cells and that LIG3 loss increases fork asymmetry. Furthermore, LIG3 depletion in BRCA1-deficient cells results in an increase in ssDNA gaps behind the replication forks, resulting in accumulation of chromosomal abnormalities. We also report that high expression of LIG3 in patients with invasive breast cancer correlates in with poorer overall survival, rendering LIG3 as a potential therapeutic target for enhancing PARPi sensitivity.

Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1-Deficient Cells by Increasing DNA Replication Stress

2020 ◽  
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Dna Replication ◽  
Nuclear Dna ◽  
Parp Inhibitor ◽  
Replication Stress ◽  
Dna Ligase ◽  
Dna Replication Stress ◽  
Inhibitor Resistance ◽  
Dna Ligase Iii

scholarly journals PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2054
Author(s):  
Elizabeth K. Lee ◽  
Ursula A. Matulonis
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Combination Therapies ◽  
Mechanisms Of Resistance ◽  
Damage Repair ◽  
Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

scholarly journals Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Carter J Barger ◽  
Linda Chee ◽  
Mustafa Albahrani ◽  
Catalina Munoz-Trujillo ◽  
Lidia Boghean ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Human Cancer ◽  
Parp Inhibitor ◽  
Bidirectional Promoter ◽  
Serous Carcinoma ◽  
Therapeutic Targeting ◽  
Recombination Repair ◽  
Dna Replication Stress ◽  
And Function ◽  
Inhibitor Resistance

The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress (RS) response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e. bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair (HR), and poly-ADP ribosylase (PARP) inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.

Abstract P068: Different treatment schemes cause distinct PARP inhibitor resistance mechanisms in BRCA2-mutant ovarian cancer cells

2021 ◽  
Author(s):  
Tzu-Ting Huang ◽  
Jayakumar R. Nair ◽  
Nitasha Gupta ◽  
Tomomi M. Yamamoto ◽  
Benjamin G. Bitler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Resistance Mechanisms ◽  
Ovarian Cancer Cells ◽  
Inhibitor Resistance

scholarly journals The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ricky M. Trigg ◽  
Liam C. Lee ◽  
Nina Prokoph ◽  
Leila Jahangiri ◽  
C. Patrick Reynolds ◽  
...  
Keyword(s):  
High Risk ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Genome Wide ◽  
High Risk Disease ◽  
Alk Positive ◽  
Inhibitor Resistance

AbstractResistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms

2020 ◽  
Vol 20 (12) ◽  
pp. 1415-1430 ◽  
Author(s):  
Qing-Shan Li ◽  
Bang-Nian Shen ◽  
Hua-Jian Xu ◽  
Ban-Feng Ruan
Keyword(s):  
Treatment Strategies ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Therapeutic Effects ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Clinical Benefits ◽  
Melanoma Patients ◽  
Inhibitor Resistance ◽  
Braf Mutant

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

scholarly journals Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps

2021 ◽  
Vol 81 (22) ◽  
pp. 4692-4708.e9
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Parp Inhibitor ◽  
Dna Ligase ◽  
Inhibitor Resistance ◽  
Dna Ligase Iii

scholarly journals Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1607
Author(s):  
Michelle McMullen ◽  
Katherine Karakasis ◽  
Ainhoa Madariaga ◽  
Amit M. Oza
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Resistance Mechanism ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Resistance Mechanisms ◽  
Cell Cycle Checkpoint ◽  
Angiogenic Therapy ◽  
Cycle Checkpoint

Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.

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