Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

Willers, Henning; Azzoli, Christopher G.; Santivasi, Wil L.; Xia, Fang

doi:10.1097/ppo.0b013e318292e4e3

Cited by 166 publications

(143 citation statements)

References 94 publications

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“…There are multiple mechanisms of radio-resistance, including resistance to IR-induced cell death (25,26). Improved understanding of the molecular mechanisms underpinning radioresistance in NSCLC is needed to enable the development of novel approaches to improve the efficacy of radiation-based treatment.…”

Section: Discussionmentioning

confidence: 99%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway.Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. KA McLaughlin et al. FLIP-mediated radio-resistance in NSCLC3

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Section: Discussionmentioning

confidence: 99%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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“…Normal replicating cells are somewhat protected from DNA damage resulting from chemotherapy due to functional cell-cycle checkpoints and DNA repair processes. Paradoxically, although a rapidly growing tumor mass may be sensitive to DNA-damaging chemotherapy, individual cancer cells are relatively tolerant of genomic damage because of resistance to cell senescence and apoptosis (2). Depending upon the functionality of each of the DNA repair pathways in a tumor, certain types of DNA damage are less well tolerated than others.…”

Section: Introductionmentioning

confidence: 99%

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

King

Diaz

McNeely

et al. 2015

Molecular Cancer Therapeutics

151

175

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CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

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“…RT is a treatment that utilizes high-energy rays or particles to destroy lung cancer cells. However, the efficacy of RT is limited due to the survival of lung cancer cells following the treatment, subsequently resulting in recurrence (4). Thus, the identification of novel therapeutic drugs to mitigate possible chemo-or radioresistance is critical to allow the development of successful lung cancer treatments.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of microRNA-133b sensitizes non-small cell lung cancer cells to irradiation through the inhibition of glycolysis

Liu

Gao

2016

Oncology Letters

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Abstract. Non-small cell lung cancer (NSCLC) accounts for 85% of all types of lung cancer and is the leading cause of world-wide cancer-associated mortalities. Radiation therapy has long been regarded as a fundamental therapeutic treatment strategy for NSCLC. However, alternative therapies for NSCLC remain insufficient, with the majority of cancers developing a high incidence of radioresistance. MicroRNAs (miRNAs/miRs) are endogenous oligonucleotide RNAs that serve an important role in carcinogenesis and tumor progression. In the present study, a novel function of miR-133b that is associated with the radiosensitivity of lung cancer cells is reported. miR-133 was downregulated in radioresistant lung cancer cells, which exhibited an elevated glycolysis rate when compared with radiosensitive cells. Additionally, it was observed that pyruvate kinase isoform M2 (PKM2) is a target of miR-133b, and that the expression of PKM2 is positively correlated with radioresistance. Finally, it was demonstrated that overexpression of miR-133b resensitizes radioresistant lung cancer cells through the inhibition of PKM2-mediated glycolysis. The current study may indicate a novel function of miR-133b, potentially aiding the development of anticancer therapeutics.

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Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

Cited by 166 publications

References 94 publications

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

Overexpression of microRNA-133b sensitizes non-small cell lung cancer cells to irradiation through the inhibition of glycolysis

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