Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application

Maione, Paolo; Sacco, Paola Claudia; Sgambato, Assunta; Casaluce, Francesca; Rossi, Antonio; Gridelli, Cesare

doi:10.1177/1758834015595048

Cited by 51 publications

(38 citation statements)

References 55 publications

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“…In the clinic, this phenomenon underlies the marked responsiveness of ALK-positive tumours to crizotinib, a multitargeted tyrosine kinase inhibitor (TKI) of ALK, ROS1 and c-MET [157]. Despite the impressive efficacy of crizotinib in the treatment of ALK-positive lung cancer, acquired resistance eventually develops in the majority of patients [158]. In a recent study, Gao et al [159] reversed EMT in a crizotinib-resistant NSCLC cell line through overexpression of miR-200c targeting ZEB1, thus providing further evidence on the role of miRNAs in mediating sensitivity of tumour cells to TKIs.…”

Section: Proliferaɵonmentioning

confidence: 99%

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Florczuk¹,

Szpechcinski²,

Chorostowska‐Wynimko³

2017

Targ Oncol

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Lung cancer is the most common cancer worldwide. Up to 85% of lung cancer cases are diagnosed as nonsmall cell lung cancer (NSCLC). The effectiveness of NSCLC treatment is expected to be improved through the implementation of robust and specific biomarkers. MicroRNAs (miRNAs) are small, non-coding molecules that play a key role in the regulation of basic cellular processes, including differentiation, proliferation and apoptosis, by controlling gene expression at the post-transcriptional level.

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Section: Proliferaɵonmentioning

confidence: 99%

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Florczuk¹,

Szpechcinski²,

Chorostowska‐Wynimko³

2017

Targ Oncol

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“…Rovalpituzumab tesirine, DLL3 targeting agent has shown encouraging results in phase I clinical trials and is now moving on to phase II studies. Several other agents are in clinical trials for treatment of lung cancer such as new generation EGFR and ALK inhibitors (174)(175)(176).…”

Section: Treatment Response and Mechanisms Of Resistancementioning

confidence: 99%

Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

Mohan¹,

Chemi²,

Brady³

2017

Transl. Lung Cancer Res.

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“…Although remarkable results have been achieved with first-/second-generation EGFR-TKIs, median progression-free survival (PFS) times do not exceed 10-12 months-that is, we encounter acquired resistance after a while [4]. Numerous genetic mutations have been identified as resistance mechanisms, and specific inhibitors are being developed against them.…”

Section: Introductionmentioning

confidence: 99%

“…The presence of these mutations indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of erlotinib and gefitinib (first-generation TKIs) and afatinib (second-generation TKIs) in first-, second-, and third-line of treatment in patients with sensitive EGFR mutations has delivered significant survival advantages, and it has become a popular treatment option commonly preferred in routine daily practice (Table 1).Although remarkable results have been achieved with first-/second-generation EGFR-TKIs, median progression-free survival (PFS) times do not exceed 10-12 months-that is, we encounter acquired resistance after a while [4]. Numerous genetic mutations have been identified as resistance mechanisms, and specific inhibitors are being developed against them.…”

mentioning

confidence: 99%

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Kazaz

Öztop

2017

Turk Thorac J

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Systemic treatment is the basic treatment approach to advanced-stage non-small-cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies. However, resistance develops against all these agents after a while. Numerous genetic mutations, T790M+ in particular, have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, third-generation EGFR-TKIs such as osimertinib and rociletinib have gained prominence due to their high level of effectiveness and low toxicity profile. Besides, systemic chemotherapy and immunotherapy are proper alternatives. A second biopsy during the progression stage and better clarification of the mechanisms causing secondary resistance will enable more successful treatments in the future. KEYWORDS:Epidermal growth factor receptor, tyrosine kinase inhibitors, resistance, non-small-cell lung cancer INTRODUCTIONLung cancer is still the primary cause of cancer-related death for both sexes worldwide, causing approximately 1.4 million deaths every year [1]. Non-small-cell lung cancer (NSCLC) cases comprise approximately 80%-85% of all lung cancers. More than half of the NSCLC cases are advanced-stage at the time of diagnosis, and those patients are characterized by poor prognosis. Systemic chemotherapy has long been employed as the primary treatment approach for advanced-stage NSCLC. Despite a series of advances in chemotherapy and the application of histology-based approaches in the course of time, median survival time does not exceed 1 year [2]. On the other hand, recent discoveries of somatic mutations in NSCLC and the employment of specific inhibitors against them have led to significant changes in the treatment of advanced-stage NSCLC. Currently, there are two key oncogenic molecular anomalies reflected in routine practice: epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase gene rearrangement.Epidermal growth factor receptor mutations are observed in approximately 10% of the whole patient group, whereas this rate may go up to 40% among Asians, non-smokers, and in patients who have adenocarcinoma histology. Deletion at exon 19 and point mutation at exon 21 (L858R) are the most common EGFR mutations [3]. The presence of these mutations indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of erlotinib and gefitinib (first-generation TKIs) and afatinib (second-generation TKIs) in first-, second-, a...

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Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application

Cited by 51 publications

References 55 publications

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

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