EGFR mutation status in pleural fluid predicts tumor responsiveness and resistance to gefitinib
Junichi SohShinichi ToyookaShuji IchiharaHiroshi SuehisaNaruyuki KobayashiSachio ItoMasaomi YamaneMotoi AoeYoshifumi SanoKatsuyuki KiuraHiroshi Date
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Treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring activating mutations in the epidermal growth factor receptor (EGFR) with EGFR-directed tyrosine kinase inhibitors (TKI) has become a paradigm for the therapeutic potential of personalized cancer treatment. Never before treatment results were reported for a defined NSCLC subgroup comparable with the outcome reported in clinical trials evaluating treatment of EGFR-mutated NSCLC with either gefitinib or erlotinib. For instance, in a recent trial of the Spanish Lung Cancer Group 217 patients with EGFR mutated advanced NSCLC were treated with erlotinib either first - or second line with a remission rate of 71%, a median time to progression (TTP) of 14 months and a median overall survival time (OS) of 27 months (1).
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The discovery of the epidermal growth factor receptor ( EGFR ) gene as the first driver gene in lung cancer has led to a major paradigm shift in lung cancer treatment. Gefitinib and other EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated excellent antitumor activity against EGFR mutation-positive non-small cell lung cancer (NSCLC). However, resistance to TKI emerged over the course of treatment, and resistance due to T790M mutations was noted in approximately half of the cases (1,2).
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Abstract Lung cancer is the leading cause of cancer deaths in the USA and worldwide and ∼85% of these cancers are of the non-small cell lung cancer (NSCLC) subtype. Approximately 10-15% of the NSCLC patients in the USA and 30-50% of these patients in Asia have tumors harboring somatic mutations in the epidermal growth factor receptor (EGFR) that cause constitutive activation of this receptor. These patients have the best clinical response to the small molecule EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Here we report that the TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) is frequently overexpressed in NSCLC tumors. We have also found that NSCLC cell lines that contain the same EGFR activating mutations found in patients express high levels of Fn14. Erlotinib treatment of these cells decreases Fn14 levels; therefore, EGFR signaling is indeed triggering Fn14 gene expression in these cell lines. Consistent with this proposal, when EGFR activation mutant receptors (L858R, ΔL747-E749, and D770-N771 insertion) were expressed in rat RL65 lung epithelial cells Fn14 expression was induced. In contrast, RL65 cells expressing a kinase-deficient EGFR receptor (D837A) did not show an increase in Fn14 expression. Since some NSCLC tumors with EGFR activating mutations acquire an additional EGFR mutation (T790M) that promotes TKI resistance, we examined Fn14 levels in a cell line containing both types of mutations. The Fn14 receptor was expressed at high levels in these cells. Finally, we found that shRNA-mediated Fn14 knockdown reduces NSCLC cell migration. Together, these data indicate that EGFR activation in NSCLC cells increases Fn14 gene expression and that Fn14 levels remain elevated in drug resistant cells. Furthermore, Fn14 may play a role in NSCLC cell motility. We propose that Fn14 may be a good biomarker for selection of NSCLC patients most likely to benefit from EGFR TKIs. It may also be a therapeutic target for NSCLC patients; in particular, for those patients with EGFR-driven tumors who have either primary or acquired resistance to EGFR tyrosine kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2011-1216
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Abstract The discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with lung cancer who had dramatic clinical responses to treatment with the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, paved the way to personalized medicine in lung cancer (1–3). Other common genomic changes that arise in lung cancers with an impact on EGFR-TKI sensitivity include KRAS and PTEN mutations, secondary T790M mutations in EGFR, and MET amplification (4–8). The retrospective and prospective studies have shown that EGFR mutations are closely associated with response, prolongation in time to progression and survival. Patients with EGFR mutations treated with gefitinib or erlotinib have a response rate of approximately 60–80%, a median time to progression in excess of nine months to one year, and a median survival in excess of two years. The prospective single arm and randomized studies of patients with previously untreated advanced non-small cell lung cancer were treated with erlotinib or either combination platinum-based combination chemotherapy versus gefitinib (9–12). The patients with EGFR mutations treated with gefitinib had a 1.5 to 2 fold longer time to progression compared to those treated with platinum-based doublet chemotherapy. The genomic changes associated with resistance to treatment with gefitinib and erlotinib are a DNA mutation which changes the threonine to methionine at the 790th amino acid of EGFR known as the (T790M) mutation as well as amplification of the MET oncogene (5, 7, 8, 13). The T790M mutation in EGFR is responsible for approximately half of the acquired resistance while MET amplification is responsible for about 20%. Irreversible inhibitors including HKI-272 and PF-299804 can cause growth inhibition in a non-small cell lung cancer with both the resistance and sensitizing mutations, while gefitinib and erlotinib do not. The phase I dose of HKI-272 has been completed and the recommended phase II dose has been tested in a randomized phase II (14). The phase II trial of HKI-272 enrolled patients previously treated with gefitinib and erlotinib and EGFR mutation testing was prospectively incorporated into the trials. PF-299804 has completed phase I testing and the phase II trials are being completed. A few patients with non-small cell lung cancer treated with chemotherapy plus either erlotinib or gefitinib have had partial responses to subsequent treatment with PF-299804. A novel covalent pyrimidine EGFR inhibitor has been identified by screening an irreversible kinase inhibitor library specifically against EGFR T790M. The agents with the lead compound (referred to as WZ 4002) are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors, gefitinib and erlotinib in vitro (15). The agent(s) are being studied and developed as potential therapeutic agents. Preclinical work has documented the non-small cell lung cancer cell line, HCC827, can be made to be resistant to gefitinib and is referred to as HCC827 GR (16). The mechanism of resistance is caused MET amplification. The in vitro and in vivo experiment have shown that joint inhibition of MET and EGFR with gefitinib plus a MET inhibitor can slow the growth of the HCC827 GR, the lung cancer cell line that developed resistance to gefitinib. Clinical trials with an EGFR inhibitor, erlotinib, with MET inhibitors are being undertaken. Investigators from Japan discovered a gene that arose from a translocation in adenocarcinomas of the lung which could transform NIH 3T3 cells (17). They discovered the transforming gene was a fusion of the ALK gene with echinoderm microtubule-associated protein-like 4 (EML4) in Japanese non-small cell lung cancers. The ALK and EML4 genes are both located in the short arm of chromosome 2 separated by 12 Mb and are oriented in opposite 5′ to 3′ directions. The translocation gives rise to a fusion gene in which the ALK tyrosine kinase is constituatively activated. Further studies have shown the translocation is present non-small cell lung cancers arising in patients from the United States and Europe. The translocated gene can now be detected by using fluorescence in situ hybridization (FSIH) in histologic sections of the tumor (18–20). There are drugs which are directed against the ALK tyrosine kinase including TAE684 and PF2341066. PF-02341066 has been tested in patients with EML4-ALK translocations in an expansion cohort of the phase I trials and has shown evidence of antitumor activity with response rates of approximately 70% in patients with this translocation (21). PF-02341066 is being tested in patients with relapsed NSCLC and EML4-ALK translocations randomized to either conventional therapy with pemetrexed or docetaxel versus PF-02341066 (ClinicalTrials.gov NCT01000025). Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL2-1
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<div>Abstract<p>Non–small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor–acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500- to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the ΔE746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance. (Cancer Res 2006; 66(19): 9601-07)</p></div>
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