Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

Tang, Joy; Salama, R; Gadgeel, Shirish M.; Sarkar, Fazlul H.; Ahmad, Aamir

doi:10.3389/fphar.2013.00015

Cited by 52 publications

(42 citation statements)

References 120 publications

(117 reference statements)

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“…TKIs such as erlotinib are effective for treatment of advanced NSCLC tumors harboring EGFR-activating mutations. However, many patients treated with erlotinib develop resistance to the targeted molecular therapy (Tang et al, 2013;Steins et al, 2014). PKC isozymes have been recognized as key effectors of known oncogenes implicated in drug resistance such as c-MET, KRAS, and TGF-b (Kermorgant et al, 2004;Sakaguchi et al, 2004;Symonds et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

Abera

Kazanietz

2015

Mol Pharmacol

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Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for advanced patients with EGFR-activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of protein kinase C (PKC) isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymallike morphology driven by transforming growth factor-b signaling. We found that H1650-M3 cells display remarkable PKCa upregulation and PKCd downregulation. Notably, silencing PKCa from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-tomesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCa RNA interference depletion and PKCd restoring sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCa in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused downregulation of PKCd expression, suggesting a unidirectional crosstalk. Finally, mechanistic studies revealed that PKCa upregulation in H1650-M3 cells is driven by transforming growth factor-b. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCa as a potential target for lung cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

Abera

Kazanietz

2015

Mol Pharmacol

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“…Patients who require complete resection and no preoperative chemotherapy usually invest in adjuvant chemotherapy. For patients with unresectable NSCLC, RT and chemotherapy are excellent options for treatment (Tang et al 2013). Further, certain agents have been combined with the chemotherapy to enhance its effects.…”

Section: Introduction: Incidence Survival Major Gene Products and Cmentioning

confidence: 99%

“…Further, certain agents have been combined with the chemotherapy to enhance its effects. The anti-vascular endothelial growth factor agent, bevacizumab, for example, when combined with chemotherapy, has resulted in increased survival rate when compared to chemotherapy treatment alone (Tang et al 2013).…”

Section: Introduction: Incidence Survival Major Gene Products and Cmentioning

confidence: 99%

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The Role of Inflammation in Lung Cancer

Gomes

Teixeira

Coelho

et al. 2014

Advances in Experimental Medicine and Biology

193

158

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Lung cancer remains a serious public health problem and is the first cause of cancer death worldwide, and the overall 5-year survival rate for all stages is 14-17 % for Non-small-cell lung cancer and 6 % for small-cell lung cancer. Clinical and epidemiologic studies have suggested a strong association among chronic infection, inflammation, and cancer. Immune system plays a critical role in maintaining tissue homeostasis, cell turnover, tissue remodeling, and preventing infection and cell transformation. The inflammatory component in the development of the neoplasm includes a diverse leukocyte population; these components are considered inflammatory tumor key factors promoting tumor progression due to its ability to release a variety of cytokines, chemokines, and cytotoxic mediators such as reactive oxygen species (ROS), metalloproteinases, interleukins, and interferons. Cancer-related inflammation affects many aspects of malignancy, including the proliferation and survival of malignant cells, angiogenesis, tumor metastasis, and tumor response to chemotherapeutic drugs and hormones. Moreover, epidemiologic studies and meta-analysis have shown that prolonged use of non-steroid anti-inflammatory (NSAID) drugs reduces the risk of several solid tumor including lung cancer. Strong lines of evidence suggest that the chemopreventive properties of chronic NSAID administration are based on their COX-inhibitory activity. However, the prevention is a much better and more economical way to fight against cancer than treating an already advanced and often incurable disease.

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“…43 They can also be used to re-sensitize cancer cells after the development of resistance, e.g., to tyrosine kinase inhibitors (TKIs). 44 The following paragraphs provide an overview of some interesting preclinical studies using epigenetic drugs in NSCLC.…”

Section: Epigenetic Therapy In Myeloid Neoplasias and Multiple Myelomamentioning

confidence: 99%

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

et al. 2016

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Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.

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Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

Cited by 52 publications

References 120 publications

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

The Role of Inflammation in Lung Cancer

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

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