Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

Pfister, Sophia X.; Markkanen, Enni; Jiang, Yanyan; Sarkar, Sovan; Woodcock, M.; Orlando, Giulia; Mavrommati, Ioanna; Pai, Chen-Chun; Zalmas, Lykourgos-Panagiotis; Drobnitzky, Neele; Dianov, Grigory L.; Verrill, Clare; Macaulay, Valentine M.; Ying, Songmin; Thangué, Nicholas B. La; D’Angiolella, Vincenzo; Ryan, Anderson J.; Humphrey, Timothy C.

doi:10.1016/j.ccell.2015.09.015

Cited by 263 publications

(239 citation statements)

References 44 publications

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“…Activation of KRAS or inhibition of WEE1 deregulates CDK activity and leads to replication stress and subsequent DNA damage (29, 30). Initial preclinical studies on AZD1775 focused on chemo-potentiation based on the rationale that disrupted cell-cycle checkpoints would allow for untimely entry into cell division with unrepaired DNA lesions, resulting in cell death (19, 31, 32).…”

Section: Discussionmentioning

confidence: 99%

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Hai

Liu

Bufe

et al. 2017

Clinical Cancer Research

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Purpose KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. Experimental Design We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment. Results We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in KRAS-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in KRAS-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1. Conclusions These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with KRAS-mutant lung cancers.

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Section: Discussionmentioning

confidence: 99%

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Hai

Liu

Bufe

et al. 2017

Clinical Cancer Research

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“…Validation of therapeutic strategies to exploit RS has recently emerged from several studies (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). For example, an SL relationship was described between oncogene-induced RS by MYC activation and ATR loss in lymphomas (49).…”

Section: Strategies For Clinical Development: Past and Presentmentioning

confidence: 99%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division, and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts, the efficacy of these classes of drugs can be impressive, but because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest. Recent progress in understanding how cancers lose control of the cell cycle, coupled with comprehensive genomic profiling of human tumor biopsies, has shown that many cancers have mutations affecting various regulators and checkpoints that impinge on the core cell-cycle machinery. These defects introduce unique vulnerabilities that can be exploited by a next generation of drugs that promise improved therapeutic windows in patients whose tumors bear particular genomic aberrations, permitting increased dose intensity and efficacy. These developments, coupled with the success of new drugs targeting cell-cycle regulators, have led to a resurgence of interest in cellcycle inhibitors. This review in particular focuses on the newer strategies that may facilitate better therapeutic targeting of drugs that inhibit the various components that safeguard the fidelity of the fundamental processes of DNA replication and repair. Clin Cancer Res; 23(13); 3232-40. Ó2017 AACR.

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“…Germline inactivation of Setd2 in mice leads to vascular remodeling defects (4), indicating a nonredundant role of SETD2 during development. Cell culture-based studies demonstrate the defects in chromosome segregation, DNA repair, and reduced nucleotide pools in SETD2-depleted cells (6)(7)(8). Mechanistic characterizations reveal that SETD2-mediated H3K36me3 regulates the recruitment of and DNMT3b to ensure the fidelity of gene transcription initiation in embryonic stem (ES) cells (9).…”

Section: Introductionmentioning

confidence: 99%