The biology and management of non-small cell lung cancer

Herbst, Roy S.; Morgensztern, Daniel; Boshoff, Chris

doi:10.1038/nature25183

Cited by 3,413 publications

(2,708 citation statements)

References 143 publications

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“…1 Combination therapy targeting different molecular key pathways is usually selected to enhance therapeutic efficacy and reduce drug resistance of cancer patients in clinics. Despite progress in new therapies, truly effective therapy is still vital for improving the survival of NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

“…1,16 In this study, we combined cisplatin with other new pathway inhibitors, mTOR and HDAC inhibitors, to treat NSCLC cancer cells. However, only cisplatin combined with pemetrexed showed significant differences in clinical outcome among the multiple cytotoxic treatments for advanced NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

“…Two major clinical types of lung cancer have been well identified, which are small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). 1 However, most patients acquire drug resistance at around 6-18 months, so continued research on new combination therapies and drug resistance mechanisms can improve the outcomes of NSCLC patients. The 5-year survival rate of most patients with metastatic NSCLC remains low.…”

Section: Introductionmentioning

confidence: 99%

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Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Chung

Tang

et al. 2019

J Cellular Molecular Medi

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These days, cancer can still not be effectively cured because cancer cells readily develop resistance to anticancer drugs. Therefore, an effective combination of drugs with different mechanisms to prevent drug resistance has become a very important issue. Furthermore, the BH3-only protein BNIP3 is involved in both apoptotic and autophagic cell death. In this study, lung cancer cells were treated with a chemotherapy drug alone or in combination to identify the role of BNIP3 and autophagy in combination chemotherapy for treating cancer. Our data revealed that various combinational treatments of two drugs could increase cancer cell death and cisplatin in combination with rapamycin or LBH589, which triggered the cell cycle arrest at the S phase. Cells with autophagosome and pEGFP-LC3 puncta increased when treated with drugs. To confirm the role of autophagy, cancer cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA). 3-MA sensitized cancer cells to chemotherapy drug treatments. These results suggest that autophagy may be responsible for cell survival in combination chemotherapy for lung cancer. Moreover, BNIP3 was induced and localized in mitochondria when cells were treated with drugs. The transfection of a dominant negative transmembrane deletion construct of BNIP3 (BNIP3ΔTM) and treatment of a reactive oxygen species (ROS) inhibitor suppressed chemo drug-induced cell death. These results indicate that BNIP3 and ROS may be involved in combination chemo drug-induced cell death. However, chemo drug-induced autophagy may protect cancer cells from drug cytotoxicity. As a result, inhibiting autophagy may improve the effects of combination chemotherapy when treating lung cancer. K E Y W O R D S autophagy, BNIP3, combination chemotherapy, reactive oxygen species How to cite this article: Chung L-Y, Tang S-J, Wu Y-C, et al. Platinum-based combination chemotherapy triggers cancer cell death through induction of Bnip3 and ROS, but not autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Chung

Tang

et al. 2019

J Cellular Molecular Medi

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“…Drug resistance is a multifaceted problem, although the mechanisms of acquired resistance of EGFR-mutant NSCLC to EGFR-TKIs have been identified, 4 little is known about the transmission of drug resistance between EGFR-TKI-resistant cells and sensitive cells and this needs to be further elucidated. However, acquired resistance is a major obstacle to the failure of targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

“…7 These resistant clones can continue to share molecular characteristics of the drug-resistant cells, contributing to a attenuated apoptotic response to subsequent therapies. Although the mechanisms of acquired resistance of EGFR-mutant NSCLC to EGFR-TKIs have been identified, 4 little is known about the transfer mechanism between EGFR-TKI-resistant cells and sensitive cells and how this transmission affect drug response needs to be further elucidated. Although the mechanisms of acquired resistance of EGFR-mutant NSCLC to EGFR-TKIs have been identified, 4 little is known about the transfer mechanism between EGFR-TKI-resistant cells and sensitive cells and how this transmission affect drug response needs to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

Exosomes transmit T790M mutation‐induced resistance in EGFR‐mutant NSCLC by activating PI3K/AKT signalling pathway

Liu

Jiang

et al. 2020

J Cellular Molecular Medi

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Emerging evidence has shown that exosomes derived from drug-resistant tumour cells are able to horizontally transmit drug-resistant phenotype to sensitive cells. However, whether exosomes shed by EGFR T790M-mutant-resistant NSCLC cells could transfer drug resistance to sensitive cells has not been investigated. We isolated exosomes from the conditioned medium (CM) of T790M-mutant NSCLC cell line H1975 and sensitive cell line PC9. The role and mechanism of exosomes in regulating gefitinib resistance was investigated both in vitro and in vivo. Exosome-derived miRNA expression profiles from PC9 and H1975 were analysed by small RNA sequencing and confirmed by qRT-PCR. We found that exosomes shed by H1975 could transfer gefitinib resistance to PC9 both in vitro and in vivo through activating PI3K/AKT signalling pathway. Small RNA sequencing and RT-PCR confirmed that miR-3648 and miR-522-3p were the two most differentially expressed miRNAs and functional study showed that up-regulation of miR-522-3p could induce gefitinib resistance in PC9 cell. The findings of our study reveal an important mechanism of acquired resistance to EGFR-TKIs in NSCLC.

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Biomarker Testing in Lung Cancer—What Does It Mean?

Borghaei

Edelman

2020

JAMA Netw Open

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The study by Leapman and colleagues 1 presents the results of an analysis of the Flatiron Health Database concentrating on the use of programmed cell death ligand 1 (PD-L1) testing and immune checkpoint inhibitors (ICIs) in patients with previously untreated, metastatic non-small cell lung cancer (NSCLC). The good news is that there has been rapid uptake of testing and use of ICIs in the appropriate population. Furthermore, as studies have been reported that expanded the indication for treatment with ICIs, practitioners quickly adopted these new approaches, frequently ahead of regulatory authorities. The bad news is that enthusiasm for these agents also led to overuse, in that a substantial proportion of patients whose PD-L1 status was less than 1 or who were untested received single-agent pembrolizumab, despite evidence that the drug was less effective than standard chemotherapy in this population.Management of patients with a diagnosis of metastatic NSCLC has changed dramatically in recent years. 2 Molecular testing using a comprehensive next-generation sequencing platform is now a standard part of our treatment algorithm, with at least 7 actionable variants known (ie, with an available US Food and Drug Administration-approved agent) and others likely to emerge in the near future. 3,4 As noted, PD-L1 testing has also become standard, based on the results of a number of studies showing an association between level of PD-L1 expression and clinical efficacy of ICIs. [5][6][7] Given this wealth of developments and increasing complexity of treatment algorithms, it is imperative that biomarker testing be correctly interpreted and used. Data from the current report 1 indicate that PD-L1 testing has had rapid uptake; however, other studies have found less use of molecular markers, such as epidermal growth factor receptor and anaplastic lymphoma kinase, among others. 4 This could be because of the ease of obtaining an immunohistochemistry-based assay, such as those for PD-L1 expression, vs the more tissue-and time-consuming process of DNA

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The biology and management of non-small cell lung cancer

Cited by 3,413 publications

References 143 publications

Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Exosomes transmit T790M mutation‐induced resistance in EGFR‐mutant NSCLC by activating PI3K/AKT signalling pathway

Biomarker Testing in Lung Cancer—What Does It Mean?

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