Combine therapy of gefitinib and fulvestrant enhances antitumor effects on NSCLC cell lines with acquired resistance to gefitinib.

Gefitinib, an EGFR receptor tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC), but the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. According to statistics, female patients, the presence of adenocarcinoma or non-smokers experienced a higher response rate. This may be involved in interaction between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR). To test whether inhibition of the ER signaling pathway affects the antitumor effect of gefitinib, gefitinib and an ER antagonist, fulvestrant, were administered to NSCLC cell lines with acquired resistance to gefitinib. Compared with treatment of either fulvestrant or gefitinib alone, drug combination obviously decreased proliferation of H1976, H1650 and PC-9 cells coming from adenocarcinoma. Rapid activations of EGFR pathway by E2β were observed in H1975 cells with T790M mutation. Additionally, EGFR and ERs expression were down-regulated respectively in response to estrogen and EGF but up-regulated in response to fulvestrant and gefitinib in vitro. These results suggest that there is a functional cross-signaling between the EGFR/ER pathways in NSCLC with acquired resistance to gefitinib, possibly providing rationale for combining gefitinib with anti-estrogen therapy for advanced NSCLC treatment.

Xu R ，Shen H ，Guo R ，Sun J ，Gao W ，Shu Y ... -  《-》

Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects.

Stabile LP ，Lyker JS ，Gubish CT ，Zhang W ，Grandis JR ，Siegfried JM ... -  《CANCER RESEARCH》

Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects.

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC). According to statistics, NSCLC patients who are female, have adenocarcinoma, or never smoked have a higher response rate to gefitinib treatment. This phenomenon could be due to the interaction between the estrogen receptor (ER) and EGFR. To test whether inhibition of the EGFR signaling pathway affects the antitumour effect of gefitinib, NSCLC cell lines were treated with gefitinib and tamoxifen, an ER antagonist. Cotreatment with gefitinib plus tamoxifen decreased the proliferation and increased the apoptosis of A549 and H1650 adencarcinoma cell lines, when compared with either drug alone. However, there was no effect on H520 cells (squamous cell carcinoma). Rapid activation of the EGFR pathway by both EGF and beta-E2 was observed in A549 cells. Additionally, EGFR and ERbeta expression was down-regulated in response to estrogen and EGF, respectively, but up-regulated in response to tamoxifen and genfitib, respectively. These results suggest that there is a functional cross-signaling between the EGFR and the ER pathways in NSCLC, possibly providing a rationale to combine gefitinib with anti-estrogen therapy for lung cancer treatment.

Shen H ，Yuan Y ，Sun J ，Gao W ，Shu YQ ... -  《-》

Everolimus synergizes with gefitinib in non-small-cell lung cancer cell lines resistant to epidermal growth factor receptor tyrosine kinase inhibitors.

Dong S ，Zhang XC ，Cheng H ，Zhu JQ ，Chen ZH ，Zhang YF ，Xie Z ，Wu YL ... -  《-》

Addition of S-1 to the epidermal growth factor receptor inhibitor gefitinib overcomes gefitinib resistance in non-small cell lung cancer cell lines with MET amplification.

Okabe T ，Okamoto I ，Tsukioka S ，Uchida J ，Hatashita E ，Yamada Y ，Yoshida T ，Nishio K ，Fukuoka M ，Jänne PA ，Nakagawa K ... -  《CLINICAL CANCER RESEARCH》