Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Matikas, Alexios; Mistriotis, Dimitrios; Georgoulias, Vassilis; Κotsakis, Athanasios

doi:10.1016/j.cllc.2014.12.013

Cited by 27 publications

(18 citation statements)

References 83 publications

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“…Acquired resistance to EGFR TKIs often results in the reactivation of signaling pathways downstream of EGFR, including the PI3K/AKT and Ras/ERK pathways [4, 5]. To determine the extent to which the addition of PLK1 inhibition enhances the effects of EGFR inhibition on canonical downstream signaling pathways, we treated PC9-ER9 and PC9-ER11 cells with erlotinib and/or volasertib and used Western blotting to assess the expression of key signaling proteins (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

et al. 2016

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial–mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.

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Section: Resultsmentioning

confidence: 99%

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

et al. 2016

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“…Pending the full publication of this trial and the results of similar studies, the continuation of EGFR TKIs in combination with chemotherapy should only be addressed in the setting of clinical trials. Monotherapies with newer generation EGFR-TKIs with more specific activity for the T790 M mutation, such as CO-1686 and AZD9291, seem to have better toxicity profiles in early clinical trials, and the results are very encouraging in patients with advanced NSCLC who develop resistance to EGFR-TKIs with a secondary T790 M mutation [36]. For the final decision regarding second-line therapy, re-biopsy might be important.…”

Section: Discussionmentioning

confidence: 98%

Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations

et al. 2015

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“…In fact, use of local therapy such as SBRT is already listed as a recognized treatment option for oligoprogression of patients with metastatic NSCLC in various review articles from across the world. [28][29][30][31][32] It is even accepted now as a treatment strategy in national consensus guidelines. 33,34 However, there remain many unknowns that only prospective randomized clinical trials can address, especially with regard to quantifying the clinical benefit of using SBRT for oligoprogression compared with simply changing or continuing with the same systemic therapy.…”

Section: Discussionmentioning

confidence: 99%

Stereotactic body radiotherapy for oligoprogressive cancer

Cheung

2016

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Stereotactic body radiotherapy (SBRT) is a focused tumour treatment that produces high local control rates with low toxicity. Its use in metastatic cancer is evolving rapidly, with purported benefits in the oligometastatic setting and for better palliation of symptomatic disease. Another potential indication for SBRT is in the setting of oligoprogression, where there is progression of a solitary or a few tumours while all other tumours are responding or stable on a systemic therapy strategy. SBRT to the progressing "rogue" tumours may delay the need to start or change systemic therapy. This may have clinical benefits including improved progression-free/overall survival and quality of life for patients. This review will summarize the limited published data. More prospective clinical trials are urgently needed to better identify and quantify the potential clinical benefits.

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Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Cited by 27 publications

References 83 publications

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations

Stereotactic body radiotherapy for oligoprogressive cancer

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