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      High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells

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          Abstract

          RAD51 recombinase plays a critical role in homologous recombination and DNA damage repair. Here we showed that expression of RAD51 is frequently upregulated in lung cancer tumors compared with normal tissues and is associated with poor survival (hazard ratio (HR) = 2, P = 0.0009). Systematic investigation of lung cancer cell lines revealed higher expression of RAD51 in KRAS mutant (MT) cells compared to wildtype (WT) cells. We further showed that MT KRAS, but not WT KRAS, played a critical role in RAD51 overexpression via MYC. Moreover, our results revealed that KRAS MT cells are highly dependent on RAD51 for survival and depletion of RAD51 resulted in enhanced DNA double strand breaks, defective colony formation and cell death. Together, our results suggest that mutant KRAS promotes RAD51 expression to enhance DNA damage repair and lung cancer cell survival, suggesting that RAD51 may be an effective therapeutic target to overcome chemo/radioresistance in KRAS mutant cancers.

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          Myc's broad reach.

          Martin Eilers, Robert Eisenman (2008)
          The role of the myc gene family in the biology of normal and cancer cells has been intensively studied since the early 1980s. myc genes, responding to diverse external and internal signals, express transcription factors (c-, N-, and L-Myc) that heterodimerize with Max, bind DNA, and modulate expression of a specific set of target genes. Over the last few years, expression profiling, genomic binding studies, and genetic analyses in mammals and Drosophila have led to an expanded view of Myc function. This review is focused on two major aspects of Myc: the nature of the genes and pathways that are targeted by Myc, and the role of Myc in stem cell and cancer biology.
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            Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

            Adrienne D. Cox, Channing J. Der, Mark Philips (2015)
            RAS proteins require membrane association for their biologic activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTI) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anticancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes, and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated posttranslational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. Clin Cancer Res; 21(8); 1819-27. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers."
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              Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice.

              L Soucek, J. Whitfield, N M Sodir … (2013)
              The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most-perhaps all-cancers, underscoring its irreplaceable role in proliferation. We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMB Rep
                Journal ID (iso-abbrev): BMB Rep
                Title: BMB Reports
                Publisher: Korean Society for Biochemistry and Molecular Biology
                ISSN (Print): 1976-6696
                ISSN (Electronic): 1976-670X
                Publication date (Print): February 2019
                Publication date (Electronic): 28 February 2019
                Volume: 52
                Issue: 2
                Pages: 151-156
                Affiliations
                [1 ]Department of pharmacy, First Affiliated Hospital of Nanchang University, Nanchang 330039, China
                [2 ]Department of Oncology, Beijing Daxing District People’s Hospital, Capital Medical University, Beijing 102600, China
                [3 ]Cancer center, Beijing Friendship Hospital, Capital Medical University, Beijing 10050, China
                [4 ]Department of respiration, First Affiliated Hospital of Nanchang University, Nanchang 330039, China
                Author notes
                [* ]Corresponding authors. Wei Zuo, Tel: +86-18170025400; Fax: +86-791-88699340; E-mail: zuowei888@ 123456tom.com ; Lei Han, Tel: +86-13482881659; Fax: +86-10-69208013; E-mail: leihan1029@ 123456gmail.com
                Article
                Publisher ID: bmb-52-151
                DOI: 10.5483/BMBRep.2019.52.2.213
                PMC ID: 6443323
                PubMed ID: 30638176
                SO-VID: 70e8e099-8b99-4db9-b6a1-1b541b1c0da9
                Copyright © Copyright © 2019 by the The Korean Society for Biochemistry and Molecular Biology
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 14 September 2018
                Date revision received : 09 October 2018
                Date accepted : 12 November 2018
                Categories
                Subject: Articles

                Keywords: dna damage repair,kras,lung cancer,myc,rad51
                Data availability:
                Keywords: dna damage repair, kras, lung cancer, myc, rad51

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