A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma

Puyol, Marta; Martín, Alberto; Dubus, Pierre; Mulero, Francisca; Pizcueta, Pilar; Khan, Gulfaraz; Guerra, Carmen; Santamarı́a, David; Barbacid, Mariano

doi:10.1016/j.ccr.2010.05.025

Cited by 378 publications

(320 citation statements)

References 36 publications

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“…3,[5][6][7] Nonetheless, Cdk4 inhibition may be effective to prevent Myc-induced skin tumors, 8 Rasinduced breast cancer 9 or K-Ras-induced non-small-cell lung carcinoma. 10 These results suggest that Cdk inhibition may be exploited in clinical settings taking into consideration the cellular context of the tumor and the pathogenic spectrum of their mutations.…”

Section: Cell Cycle Entrymentioning

confidence: 99%

“…For instance, inhibition of Cdk4 prevents the development of lung tumors induced by K-Ras oncogene by triggering senescence, a permanent arrest in G0/G1. 10 Current data suggest that senescent cells may be cleared by an innate immune response, but the extent to which this may contribute to prevention of age-related pathologies and cancer is currently not clear.…”

Section: Cell Cycle Entrymentioning

confidence: 99%

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Killing cells by targeting mitosis

2012

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Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis.As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.

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Section: Cell Cycle Entrymentioning

confidence: 99%

Section: Cell Cycle Entrymentioning

confidence: 99%

Killing cells by targeting mitosis

2012

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“…In further support of this emerging theme, Amati and colleagues (Campaner et al 2010) observed that oncogenic stress caused by the Myc oncoprotein sensitizes Cdk2-deficient cells to undergo senescence in vitro and in vivo. Similarly, in advanced non-small-cell lung carcinoma driven by activation of oncogenic KRas, tumor progression is halted and senescence is induced upon genetic ablation of Cdk4 (Puyol et al 2010). The rising number of examples of enforced senescence in vivo justifies further exploration of this possibility by addressing several more clinically oriented questions.…”

Section: Restoration Of Cellular Senescence In Vivomentioning

confidence: 99%

The essence of senescence: Figure 1.

Kuilman¹,

Michaloglou²,

Mooi³

et al. 2010

Genes Dev.

1,839

1,771

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Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of “cellular senescence” in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression. Additionally, we highlight the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo.

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“…KRAS mutations are negative prognostic indicators in NSCLC (10) and have been associated with poor response to drugs targeting EGFR in NSCLC and colorectal carcinoma (10)(11)(12). Despite many attempts, pharmacologic targeting of KRAS remains a challenge (13)(14)(15)(16)(17)(18). Recent studies have identified alterations in metabolic programming that are specific to RASmutant cells such as enhanced glucose uptake, decreased tricarboxylic acid (TCA) cycle activity and higher dependency on glutamine for biosynthetic reactions than RAS wild-type cells (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Moran

Trusk

Pry

et al. 2014

Molecular Cancer Therapeutics

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KRAS gene mutation is linked to poor prognosis and resistance to therapeutics in non-small cell lung cancer (NSCLC). In this study, we have explored the possibility of exploiting inherent differences in KRAS-mutant cell metabolism for treatment. This study identified a greater dependency on folate metabolism pathways in KRAS mutant compared with KRAS wild-type NSCLC cell lines. Microarray gene expression and biologic pathway analysis identified higher expression of folate metabolism-and purine synthesis-related pathways in KRASmutant NSCLC cells compared with wild-type counterparts. Moreover, pathway analysis and knockdown studies suggest a role for MYC transcriptional activity in the expression of these pathways in KRAS-mutant NSCLC cells. Furthermore, KRAS knockdown and overexpression studies demonstrated the ability of KRAS to regulate expression of genes that comprise folate metabolism pathways. Proliferation studies demonstrated higher responsiveness to methotrexate, pemetrexed, and other antifolates in KRAS-mutant NSCLC cells. Surprisingly, KRAS gene expression is downregulated in KRAS wild-type and KRAS-mutant cells by antifolates, which may also contribute to higher efficacy of antifolates in KRAS-mutant NSCLC cells. In vivo analysis of multiple tumorgraft models in nude mice identified a KRAS-mutant tumor among the pemetrexedresponsive tumors and also demonstrated an association between expression of the folate pathway gene, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), and antifolate activity. Collectively, we identify altered regulation of folate metabolism in KRAS-mutant NSCLC cells that may account for higher antifolate activity in this subtype of NSCLC. Mol Cancer Ther; 13(6); 1611-24. Ó2014 AACR.

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A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma

Cited by 378 publications

References 36 publications

Killing cells by targeting mitosis

Killing cells by targeting mitosis

The essence of senescence: Figure 1.

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

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