Combination Erlotinib-Cisplatin and Atg3-Mediated Autophagy in Erlotinib Resistant Lung Cancer

Lee, Jasmine G.; Wu, Reen

doi:10.1371/journal.pone.0048532

Cited by 36 publications

(46 citation statements)

References 63 publications

(51 reference statements)

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“…14,17,18 Although it is known that cancer cells with Ras mutations are addicted to upregulated autophagic flux, 10,11,13,14 little has been done to clarify the role of autophagy in EGFR-driven carcinoma cells. 19,20 In this study, we demonstrate that gefitinib-resistant (GR) EGFR-mutant lung carcinoma cells with an EMT phenotype can survive under hypoxic conditions in vitro in the absence of EGFR T790M mutation or Met, EGFR, or AXL activity because of enhanced autophagic flux. Furthermore, using immunohistochemistry and electron microscopy, we also demonstrate cytoplasmic, granular expression of LC3A (an isoform of LC3) in untreated EGFR-mutant lung cancer tissues, as well as the formation of autophagosomes in these cells.…”

mentioning

confidence: 77%

“…13,14 Autophagy has been recently reported to have a key role in the acquired resistance to erlotinib in PC9 cells, another EGFR-mutant lung adenocarcinoma cell line. 19 Furthermore, one report shows that erlotinib induces autophagy as well as apoptosis in parental HCC827 and HCC4006 cells, and that inhibiting autophagy significantly enhances sensitivity to erlotinib in both cell lines. 20 These findings are analogous to those already reported in chronic myeloid leukemia cells, where suppression of autophagy can potentiate apoptotic cell death induced by imatinib, a potent Abl TKI.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFRmutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

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mentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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“…This is in line with previous articles, including ours, that have demonstrated the dependence of EGFR TKI-resistant lung carcinoma cells upon augmented autophagy. 6,27,28 It seems that EGFR-mutated carcinoma cells that have lost dependence on kinase activity usually exhibit enhanced autophagic flux as a compensatory mechanism for survival. Therefore, autophagy inhibition might be effective at eradicating TKI-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial–mesenchymal transition phenotype

Sakuma

Nishikiori

Hirai

et al. 2016

Laboratory Investigation

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The secondary epidermal growth factor receptor (EGFR) T790M mutation is the most prominent mechanism that confers resistance to first-or second-generation EGFR tyrosine kinase inhibitors (TKIs) in lung cancer treatment. Although third-generation EGFR TKIs can suppress the kinase activity of T790M-positive EGFR, they still cannot eradicate EGFR-mutated cancer cells. We previously reported that a subpopulation of EGFR-mutant lung adenocarcinomas depends on enhanced autophagy, instead of EGFR, for survival, and in this study we explore another mechanism that contributes to TKI resistance. We demonstrate here that an EGFR-mutant lung adenocarcinoma cell line, H1975 (L858R+T790M), has a subset of cells that exhibits an epithelial-mesenchymal transition (EMT) phenotype and can thrive in the presence of third-generation EGFR TKIs. These cells depend on not only autophagy but also on the isomerase Pin1 for survival in vitro, unlike their parental cells. The Pin1 protein was expressed in an EGFR-mutant lung cancer tissue that has undergone partial EMT and acquired resistance to EGFR TKIs, but not its primary tumor. These findings suggest that inhibition of Pin1 activity can be a novel strategy in lung cancer treatment. Lung adenocarcinomas with an activating mutation in the epidermal growth factor receptor (EGFR) gene depend on EGFR signaling for survival and proliferation. Although most EGFR-mutant lung cancers initially respond to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, or afatinib, disease progression almost inevitably develops, on average, 1 year after the initiation of TKI therapy. The most common mechanism of acquired resistance is the secondary EGFR T790M mutation, which is found in 50-60% of resistant tumors. 1 To overcome T790M-mediated resistance, third-generation EGFR TKIs, including CO-1686 (also known rociletinib) and AZD9291, have been developed. 2,3 These drugs have potent activity against both the common EGFR mutations (inframe deletions in exon 19 and the L858R mutation in exon 21) and the T790M mutation. Recent early-phase clinical trial data demonstrated a response rate of 60% in patients with T790M-positive tumors. 4,5 Although this response rate was much higher than that of patients with T790M-negative tumors (21-29%), acquired resistance to these agents has emerged even in T790M-positive tumors. 4,5 We previously reported that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, have subpopulations of cells that display an epithelial-mesenchymal transition (EMT) phenotype and depend on enhanced autophagy, but not on EGFR activity, for survival. 6 We surmise that these EGFR-mutant cells devoid of EGFR dependency lie at the root of TKI resistance.Protein phosphorylation is a fundamental mode of intracellular signaling in many cellular processes such as proliferation and differentiation. The peptidyl-prolyl isomerase Pin1 has been identified as a regulator that catalyzes cis-trans isomerization of phosphorylated Ser/Thr-Pro motifs in a subset of phosphoryla...

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“…The overexpression of EGFR in tumors has been linked to poor prognosis due to its association with tumor progression, angiogenesis, migration, and metastasis (Yarden, 2001; Mehta, 2012). Erlotinib is highly utilized in cancer therapy due to its relatively few side-effects and high efficacy in patient responders of this TKI (Lee and Wu, 2012). Initially, erlotinib was approved in 2004 as monotherapy for patients with NSCLC, and then in 2005, it was approved as for combination chemotherapy with gemcitabine (Wheeler et al, 2010).…”

Section: Erlotinibmentioning

confidence: 99%

“…A recent study investigated the efficacy of a low-dose combination treatment of erlotinib and cisplatin in lung adenocarcinoma to better comprehend the role of autophagy in erlotinib resistance (Lee and Wu, 2012). Exploring the relationship between drug resistance and cell autophagy is important because autophagy functions in cell protein homeostasis and degradation of injured cellular organelles (Hsieh et al, 2009).…”

Section: Combination Therapy To Improve Treatment With Erlotinibmentioning

confidence: 99%

Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

Tang¹,

Salama²,

Gadgeel³

et al. 2013

Front. Pharmacol.

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Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options.

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Combination Erlotinib-Cisplatin and Atg3-Mediated Autophagy in Erlotinib Resistant Lung Cancer

Cited by 36 publications

References 63 publications

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial–mesenchymal transition phenotype

Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

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