Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib.

Janjigian, Y. Y.; Groen, Harry J.M.; Horn, Leora; Smit, Egbert F.; Fu, Yan; Wang, F.; Shahidi, Mehdi; Denis, L.; Pao, William; Miller, V. A.

doi:10.1200/jco.2011.29.15_suppl.7525

Cited by 118 publications

(64 citation statements)

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“…Then, it is necessary to have a treatment option for these CAEs, without decreasing the benefit of this combination. It has been previously reported that rash can be a surrogate of treatment benefit with a TKI (21). In our study we did not observe any relationship between skin toxicities and outcomes, but this could be explained because treatment with tetracycline may modify the pathophysiology of these toxicities, reducing their incidence and severity.…”

contrasting

confidence: 41%

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Skin communicates what we deeply feel: antibiotic prophylactic treatment to reduce epidermal growth factor receptor inhibitors induced rash in lung cancer (the Pan Canadian rash trial)

et al. 2016

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contrasting

confidence: 41%

“…Moreover, in a setting in which patients treated with a TKI may develop resistance and may need combined treatments that can trigger skin toxicities, such as cetuximab plus afatinib (21). Then, it is necessary to have a treatment option for these CAEs, without decreasing the benefit of this combination.…”

mentioning

confidence: 99%

Skin communicates what we deeply feel: antibiotic prophylactic treatment to reduce epidermal growth factor receptor inhibitors induced rash in lung cancer (the Pan Canadian rash trial)

et al. 2016

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“…For example, using mouse lung tumor models of drug-sensitive and -resistant EGFR-mutant alleles, we previously showed that dual inhibition of EGFR with the second-generation EGFR TKI afatinib plus the anti-EGFR antibody cetuximab could eradicate T790M-driven tumors (40). A trial based on these data has now shown a 40% partial response rate in patients with acquired resistance (41).…”

Section: Discussionmentioning

confidence: 99%

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Ohashi

Sequist

Arcila³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

400

333

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Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/ BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

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“…However, none of these agents alone does maximally suppress EGFR signaling, as also shown in our experiments. The combination of afatinib and cetuximab has been reported to overcome T790M resistance both preclinically [19] and clinically [20]. Regales et al [19] found that dual targeting of EGFR with afatinib and cetuximab could induce regression of H1975 cell xenografts and thus overcome the major drug resistant T790M mutation.…”

Section: Discussionmentioning

confidence: 99%

“…The strongest combinational activity was observed at supra micro molar doses of afatinib. The combination of afatinib and cetuximab has been reported to overcome resistance due to T790M mutation both in vivo [19] as well as clinically [20]. We then tested the combinational effect of afatinib and cetuximab on H1975 cells in vitro.…”

Section: Effect Of Adding T790m-specific-sirnas To Either Egfr Tkis Omentioning

confidence: 99%

Effect of siRNAs targeting the EGFR T790M mutation in a non-small cell lung cancer cell line resistant to EGFR tyrosine kinase inhibitors and combination with various agents

Chen

Kronenberger

Teugels

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tThe epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, some mutations confer resistance to current available agents, especially the frequently occurring T790M mutation. In the current study, we have examined, in a NSCLC cell line H1975 containing both L858R and T790M mutations, the effect of T790M-specific-siRNAs versus other EGFR-specific-siRNAs. T790M-specific-siRNAs were able to inhibit T790M and EGFR mRNA, to reduce EGFR protein expression, as well as to reduce the cell growth and induce cell caspase activity in H1975 cells. However, this effect showed less potency compared to the other EGFR-specific-siRNAs. EGFR-specific-siRNAs strongly inhibited cell growth and induced apoptosis in H358, H1650, H292, HCC827 and also in H1975 cells, which showed weak response to tyrosine kinase inhibitors (TKIs) or cetuximab. The addition of T790M-specific-siRNAs could rescue the sensitivity of T790M mutant H1975 cells to TKIs. The combination of T790M-specific-siRNAs and cetuximab also additively enhanced cell growth inhibition and induction of apoptosis in H1975 cells. Among the anti-EGFR agents tested, the strongest biological effect was observed when afatinib was combined with T790M-specific-siRNAs. Afatinib also offered extra effect when combined with cetuximab in H1975 cells. In conclusion, knock-down of T790M transcript by siRNAs further decreases the cell growth of T790M mutant lung cancer cells that are treated with TKIs or cetuximab. The combination of a potent, irreversible kinase inhibitor such as afatinib, with T790M-specific-siRNAs should be further investigated as a new strategy in the treatment of lung cancer containing the resistant T790M mutation.

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Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib.

Cited by 118 publications

References 0 publications

Skin communicates what we deeply feel: antibiotic prophylactic treatment to reduce epidermal growth factor receptor inhibitors induced rash in lung cancer (the Pan Canadian rash trial)

Skin communicates what we deeply feel: antibiotic prophylactic treatment to reduce epidermal growth factor receptor inhibitors induced rash in lung cancer (the Pan Canadian rash trial)

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Effect of siRNAs targeting the EGFR T790M mutation in a non-small cell lung cancer cell line resistant to EGFR tyrosine kinase inhibitors and combination with various agents

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