A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non–Small-Cell Lung Cancer

Goldberg, Sarah B.; Supko, Jeffrey G.; Neal, Joel W.; Muzikansky, Alona; Digumarthy, Subba R.; Fidias, P.; Temel, Jennifer S.; Heist, Rebecca S.; Shaw, Alice T.; McCarthy, Patricia C.; Lynch, Thomas J.; Sharma, Sreenath V.; Settleman, Jeffrey; Sequist, Lecia V.

doi:10.1097/jto.0b013e318262de4a

Cited by 145 publications

(102 citation statements)

References 28 publications

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“…By far, numbers of basic studies and clinical trials evaluating such effect in cancer treatment are in progress [11,19,20,21,22,23,24,25,26]. However, the published results were in conflict.…”

Section: Introductionmentioning

confidence: 57%

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Liu²,

Liu³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a poor prognosis. Combination treatment of autophagy inducer and autophagy inhibitor may be a feasible solution to improve the therapeutic effects. However, the correlation between them is unclear. The purpose of this study was to investigate the effect of autophagy inhibition at different stages on cytotoxicity of autophagy inducers in glioblastoma cells. Methods: Autophagy inhibition at early stage was achieved by 3-methyladenine (3-MA) or Beclin 1 shRNA. Autophagy inhibition at late stage was achieved by chloroquine (CQ) or Rab7 shRNA. Cell viability was assessed by MTT assay. Autophagy was measured using transmission electron microscopy and western blot. Apoptosis was measured using western blot and flow-cytometry. Results: Inhibition of early steps of autophagy by 3-MA or Beclin 1 knockdown decreased the toxic effect of arsenic trioxide (ATO) in GBM cell lines. In contrast, blockade of autophagy flux at late stage by CQ or Rab7 knockdown enhanced the cytotoxicity of ATO, and caused accumulation of degradative autophagic vacuoles and robust apoptosis. Moreover, depletion of Beclin 1 abolished the synergistic effect of ATO and CQ by reducing autophagy and apoptosis. Combination of CQ with other autophagy inducers also induced synergistic apoptotic cell death. Conclusion: These results suggest that inhibition of late process of autophagy, not initial step, increases the cytotoxic effect of autophagy inducers via autophagy and apoptosis, which may contribute to GBM chemotherapy.

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Section: Introductionmentioning

confidence: 57%

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Liu²,

Liu³

et al. 2015

Cell Physiol Biochem

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“…2,15 The most well-known example is selection of patients eligible for EGFR inhibition in metastatic lung cancer based on KRAS and EGFR mutational status. 3,5,[16][17][18][19] In this article, we compared the performance of five technical platforms for detecting mutations in FFPE-derived tumor DNA. All platforms, except the NGS-454, detected the (clinically relevant) mutations originally detected by the reference method.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Next-Generation Sequencing and Mutation-Specific Platforms in Clinical Practice

Hinrichs

Blokland

Moons

et al. 2015

American Journal of Clinical Pathology

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“…Meanwhile, in non-small cell lung tumor with the expression of wild-type EGFR, the combined use of chloroquine and erlotinib could overcome the resistance to erlotinib, and the use of gefitinib in combination can also increase the toxicity of gefitinib. The clinical phase I experiment of the combined use of chloroquine and erlotinib showed that the combined use of the two has good tolerance [39-41]. Therefore, the combination of CH12 and an autophagy inhibitor to treat EGFRvIII-positive hepatocellular carcinoma is worth further exploration.…”

Section: Discussionmentioning

confidence: 99%

The Effect of and Mechanism Underlying Autophagy in Hepatocellular Carcinoma Induced by CH12, a Monoclonal Antibody Directed Against Epidermal Growth Factor Receptor Variant III

Song

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epidermal growth factor receptor variant III (EGFRvIII), the most frequent EGFR variant, is constitutively activated without binding to EGF and is correlated with a poor prognosis. CH12, a human-mouse chimeric monoclonal antibody, has been developed in our laboratory and selectively binds to overexpressed EGFR and EGFRvIII. A previous study had reported that EGFR could influence autophagic activity, and autophagy is closely related to tumor development and the response to drug therapy. In this study, we aimed to elucidate the effect of CH12 on autophagy and efficacy of combining CH12 with an autophagy inhibitor against EGFRvIII-positive tumors. Methods: EGFRvIII was overexpressed in liver cancer, glioblastoma and breast cancer, and the change in the autophagy-relevant protein levels was analyzed by western blot assays, LC3 punctate aggregation was analyzed by immunofluorescence. The interaction of Beclin-1 and Rubicon was assessed by co-immunoprecipitation (Co-IP) after CH12 treatment. The efficacy of ATG7 or Beclin-1 siRNA in combination with CH12 in Huh-7-EGFRvIII cells was assessed by CCK-8 assays. The autophagy and apoptosis signaling events in Huh-7-EGFRvIII cells upon treatment with control, CH12, siRNA or combination for 48 h were assessed by western blot assays. Results: Our results showed that, in cancer cell lines overexpressing EGFRvIII, only the liver cancer cell lines Huh-7 and PLC/PRF/5 suggested autophagy activation. We then investigated the mechanism of autophagy activation after EGFRvIII overexpression. The results showed that EGFRvIII interacted with Rubicon, an autophagy inhibition protein, and released Beclin-1 to form the inducer complex, thus contributing to autophagy. In addition, CH12, via inhibiting the phosphorylation of EGFRvIII, promoted the interaction of EGFRvIII with Rubicon, further inducing autophagy. In vitro assays suggested that knocking down the expression of the key proteins ATG7 or Beclin-1 in the autophagy pathway with siRNA inhibits tumor cell proliferation. Combining autophagy-related proteins 7 (ATG7) or Beclin-1 siRNA with CH12 in Huh-7-EGFRvIII cells showed better inhibition of cell proliferation. Conclusion: EGFRvIII could induce autophagy, and CH12 treatment could improve autophagy activity in EGFRvIII-positive liver cancer cells. The combination of CH12 with an autophagy inhibitor or siRNA against key proteins in the autophagy pathway displayed more significant efficacy on EGFRvIII-positive tumor cells than monotherapy, and induced cell apoptosis.

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A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non–Small-Cell Lung Cancer

Cited by 145 publications

References 28 publications

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Comparison of Next-Generation Sequencing and Mutation-Specific Platforms in Clinical Practice

The Effect of and Mechanism Underlying Autophagy in Hepatocellular Carcinoma Induced by CH12, a Monoclonal Antibody Directed Against Epidermal Growth Factor Receptor Variant III

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