Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

Ninomiya, Takashi; Takigawa, Nagio; Ichihara, Eiki; Ochi, Nobuaki; Murakami, Toshi; Honda, Yoshihiro; Kubo, Toshio; Minami, Daisuke; Kudo, Kenichiro; Tanimoto, Mitsune; Kiura, Katsuyuki

doi:10.1158/1535-7163.mct-12-0885

Cited by 59 publications

(51 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that IC50 values were 0.28 nM for PC-9, 350.0 nM for PC-9-GR, 38.4nM for H1975 and 2.3μM for H460 cells, respectively. These results suggest that NSCLC cells with T790M mutant EGFR are relatively sensitive to afatinib than cells carrying wild-type EGFR, which is consistent with the reports from previous study [16]. Of note, we found that IC50 value of PC-9-GR cells were significantly higher than that of parental PC-9 cells, indicating that development of acquired resistance to gefitinib, or to other first-generation of TKIs, may also cause reduced sensitivity to second-generation of TKIs in NSCLC cells that were initially sensitive to these agents (Figure 2).…”

Section: Resultssupporting

confidence: 93%

Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

et al. 2015

View full text Add to dashboard Cite

Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation.

show abstract

Section: Resultssupporting

confidence: 93%

Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Viable cells were measured using the modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) assay (21,22).…”

Section: Drug Sensitivity Assaysmentioning

confidence: 99%

Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases

et al. 2016

Self Cite

View full text Add to dashboard Cite

Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinibresistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.

show abstract

“…2) (Zhang et al 2006). Inhibition of autophosphorylation by afatinib has been shown for EGFR (Ioannou et al 2013; Kim et al 2012b; Ninomiya et al 2013; Solca et al 2012; Takezawa et al 2012; Tanaka et al 2012), HER2 (Canonici et al 2013; Ninomiya et al 2013; Solca et al 2012; Tabara et al 2012; Takezawa et al 2012; Tanaka et al 2012), ErbB4 (Solca et al 2012) and transphosphorylation of ErbB3 (Ioannou et al 2013; Kim et al 2012b; Tabara et al 2012; Takezawa et al 2012; Tanaka et al 2012) in a wide variety of cell lines representing lung (Kim et al 2012b; Lee et al 2013; Ninomiya et al 2013; Solca et al 2012; Tabara et al 2012; Takezawa et al 2012), breast (Solca et al 2012), gastric (Tanaka et al 2012), colorectal (Khelwatty SA, Essapen S, Seddon A, Modjtahedi H, in preparation) and pancreatic cancer (Ioannou et al 2013). Similar to the kinase inhibition studies, afatinib’s potency for inhibition of autophosphorylation was in the low nanomolar range.…”

Section: Effects At the Cellular Levelmentioning

confidence: 99%

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

Modjtahedi

Cho

Michel

et al. 2014

Naunyn-Schmiedeberg's Arch Pharmacol

102

View full text Add to dashboard Cite

Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto-and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR-or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.

show abstract

Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

Cited by 59 publications

References 33 publications

Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

Contact Info

Product

Resources

About