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Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways.

ABSTRACT: DNA double-strand breaks are the critical lesions responsible for the majority of ionizing radiation-induced cell killing. Thus, the ability of tumor cells to elicit a DNA damage response following radiation, via activation of DNA repair and cell-cycle checkpoints, promotes radiation resistance and tumor cell survival. Consequently, agents that target these DNA damage response pathways are being developed to overcome radiation resistance. Overall, these agents are effective radiosensitizers; however, their mechanisms of tumor cell selectivity are not fully elucidated. In this review, we focus on the crucial radiation-induced DNA damage responses as well as clinical and translational advances with agents designed to inhibit these responses. Importantly, we describe how synthetic lethality can provide tumor cell-selective radiosensitization by these agents and expand the therapeutic window for DNA damage response-targeted agents used in combination with radiotherapy.

SUBMITTER: Morgan MA

PROVIDER: S-EPMC4494107 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways.

Morgan Meredith A MA Lawrence Theodore S TS

Clinical cancer research : an official journal of the American Association for Cancer Research 20150701 13

DNA double-strand breaks are the critical lesions responsible for the majority of ionizing radiation-induced cell killing. Thus, the ability of tumor cells to elicit a DNA damage response following radiation, via activation of DNA repair and cell-cycle checkpoints, promotes radiation resistance and tumor cell survival. Consequently, agents that target these DNA damage response pathways are being developed to overcome radiation resistance. Overall, these agents are effective radiosensitizers; how ...[more]

PMID: 26133775

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Project description:Opinion statementMetastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.

Dataset Information

Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways.

Publications

Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways.

Similar Datasets

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