Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

Murai, Junko; Feng, Ying; Yu, Guoying Karen; Ru, Yuanbin; Tang, Sai-Wen; Shen, Yuqiao; Pommier, ﻿Yves

doi:10.18632/oncotarget.12266

Cited by 234 publications

(270 citation statements)

References 58 publications

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“…A distinct mechanism, high expression levels of schlafen family member 11 (SLFN11), has been identified as a critical determinant of PARP-inhibitor sensitivity in SCLC cell lines and patient-derived xenografts 92,93 . SLFN11 is actively recruited to sites of DNA damage, inhibits HR 94 , and activates a cellular replication-stress response 93 .…”

Section: Potential Therapeutic Targets In Sclcmentioning

confidence: 99%

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Unravelling the biology of SCLC: implications for therapy

et al. 2017

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Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are being clinically tested in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints. Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaetescute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

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Section: Potential Therapeutic Targets In Sclcmentioning

confidence: 99%

“…SLFN11 is actively recruited to sites of DNA damage, inhibits HR 94 , and activates a cellular replication-stress response 93 . Notably, SLFN11 expression correlates with sensitivity to DNA-damaging agents (such as irinotecan, etoposide, and cisplatin) in other malignancies 95–98 .…”

Section: Potential Therapeutic Targets In Sclcmentioning

confidence: 99%

Unravelling the biology of SCLC: implications for therapy

et al. 2017

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“…There was no correlation between either biomarker with response although a trend to high SLFN11 expression and better overall survival was observed. SLFN11 is actively recruited to sites of DNA damage, inhibiting HR respectively) [54] and activating a cellular replication-stress response [55,56]. SLFN11 suppression has been associated with chemoresistance in SCLC models [57] and identified as a biomarker of PARP inhibitor response in SCLC PDX [44].…”

Section: Veliparibmentioning

confidence: 99%

Targeting DNA damage in SCLC

et al. 2017

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A B S T R A C TSCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's.The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints.Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy.This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.

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“…PARP1, an E2F1 co-activator, involved in DNA repair was highly expressed at both the mRNA and protein levels in SCLC, leading to the hypothesis and preclinical validation that PARP inhibition downregulated key DNA repair mechanisms leading to enhanced efficacy of chemotherapy and perhaps other DNA damaging therapies (62). Schlafen family member 11 (SLFN11) has been identified as a critical determinant of PARP inhibitor sensitivity in SCLC cell lines and patient-derived xenografts (84,85). SLFN11 is actively recruited to sites of DNA damage, inhibits HR and activates a replication stress response (85).…”

Section: Parp Inhibitionmentioning

confidence: 99%

“…Schlafen family member 11 (SLFN11) has been identified as a critical determinant of PARP inhibitor sensitivity in SCLC cell lines and patient-derived xenografts (84,85). SLFN11 is actively recruited to sites of DNA damage, inhibits HR and activates a replication stress response (85). High SLFN11 expression is associated with improved tumor response, progression free survival and overall survival in SCLC patients treated with temozolomide and the PARP inhibitor veliparib in a recent randomized phase II clinical trial (86).…”

Section: Parp Inhibitionmentioning

confidence: 99%

Relevance of genetic alterations in squamous and small cell lung cancer

Sabari

Paik

2017

Ann. Transl. Med.

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Abstract:The precision medicine revolution has led to the development and US FDA approval of multiple targeted therapies in non-squamous non-small cell lung cancers, including tyrosine kinase inhibitors targeting EGFR, ALK, and ROS1. However, the development of targeted therapies for squamous cell lung cancers (SQCLCs) and small cell lung cancers (SCLCs) has lagged behind and the mainstay of systemic therapy for most patients with metastatic disease remains chemotherapy; which has seen little meaningful progress over the past three decades. The ideal of precision medicine in these diseases may appear elusive; however, recent comprehensive genomic analysis of SQCLC and SCLC has led to multiple breakthroughs in our understanding of the biology of these diseases and has led to new therapeutic approaches currently under active clinical investigation. This review will focus on the therapeutic relevance of these alterations in their respective diseases and new insights into promising therapeutics currently under investigation.

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Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

Cited by 234 publications

References 58 publications

Unravelling the biology of SCLC: implications for therapy

Unravelling the biology of SCLC: implications for therapy

Targeting DNA damage in SCLC

Relevance of genetic alterations in squamous and small cell lung cancer

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