Simultaneous targeting of MET overexpression in EGFR mutation-positive non-small cell lung cancer can increase the benefit of EGFR-TKI therapy?
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ABSTRACT:
SUBMITTER: Kanemura H
PROVIDER: S-EPMC7481636 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Simultaneous targeting of MET overexpression in <i>EGFR</i> mutation-positive non-small cell lung cancer can increase the benefit of EGFR-TKI therapy?
Kanemura Hiroaki H Takeda Masayuki M Nakagawa Kazuhiko K
Translational lung cancer research 20200801 4
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Project description:Patients from Asia with non-small-cell lung cancer (NSCLC) often have mutations in the epidermal growth factor receptor (EGFR) gene. While an increasing number of EGFR tyrosine kinase inhibitors (TKIs) are now available for patients with EGFR mutation-positive NSCLC, most patients inevitably develop resistance to the treatment. Evidence from clinical studies suggests that treatment outcomes and resistance mechanisms vary depending on the choice of TKI therapy in the first-line setting. Hence, it is important to develop optimal treatment sequencing strategies that can provide maximum survival benefit for the patient. In this review we present clinical evidence in Asian patients with NSCLC for various EGFR TKIs, with the goal of supporting the optimization of treatment sequencing.
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Project description:After the discovery of activating mutations in EGFR, EGFR tyrosine kinase inhibitors (TKIs) have been introduced into the first-line treatment of non-small-cell lung cancer (NSCLC). A series of studies have shown that EGFR TKI monotherapy as first-line treatment can benefit NSCLC patients harbouring EGFR mutations. Besides, combination strategies based on EGFR TKIs in the first line treatment have also been proved to delay the occurrence of resistance. In this review, we summarize the scientific literature and evidence of EGFR TKIs as first-line therapy from the first-generation EGFR TKIs to conceptually proposed fourth-generation EGFR TKI, and also recommend the application of monotherapy and combination therapies of the EGFR-based targeted therapy with other agents such as chemotherapy, anti-angiogenic drugs and immunecheckpoint inhibitors.
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Project description:Treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutation with EGFR-TKIs has achieved great success, yet faces the development of acquired resistance as the major obstacle to long-term disease remission in the clinic. MET (or c-MET) gene amplification has long been known as an important resistance mechanism to first- or second-generation EGFR-TKIs in addition to the appearance of T790 M mutation. Recent preclinical and clinical studies have suggested that MET amplification and/or protein hyperactivation is likely to be a key mechanism underlying acquired resistance to third-generation EGFR-TKIs such as osimertinib as well, particularly when used as a first-line therapy. EGFR-mutant NSCLCs that have relapsed from first-generation EGFR-TKI treatment and have MET amplification and/or protein hyperactivation should be insensitive to osimertinib monotherapy. Therefore, combinatorial therapy with osimertinib and a MET or even a MEK inhibitor should be considered for these patients with resistant NSCLC carrying MET amplification and/or protein hyperactivation.
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Project description:Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI.
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Project description:Few treatment options are available for brain metastases (BMs) in EGFR-mutant non-small cell lung cancer (NSCLC) that progress with prior EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) therapy in these patients. NSCLC patients with confirmed sensitive EGFR mutations and BMs were retrospectively reviewed. All patients experienced failure of EGFR-TKI therapy and were divided into two cohorts based on subsequent treatment. Cohort 1 included patients who received ICI therapy, while cohort 2 included patients treated with chemotherapy. Overall and intracranial objective response rates (ORRs) were used to evaluate the treatment response. Overall and intacranial progression-free survival (PFS) were calculated by Kaplan-Meier analysis and compared with the log-rank test. Univariate and multivariate Cox analyses were used to identify prognostic factors. A total of 53 patients treated with ICI therapy and 40 patients treated with chemotherapy were included in cohorts 1 and 2, respectively. In cohort 1, the overall ORR was 20.8%, with a median overall PFS of 4.2 months. The median intracranial PFS was 5.1 months. Of the 38 patients with measurable intracranial lesions, the intracranial ORR was 21.0%. Patients who received ICI combined with chemotherapy had the highest intracranial ORR of 37.5%. Compared to patients treated with chemotherapy in cohort 2, patients receiving ICI combined with chemotherapy had both longer intracranial PFS (6.4 vs. 5.1 months, p = 0.110) and overall PFS (6.2 vs. 4.6 months, p = 0.054), and these differences approached statistical significance. Univariate and multivariate Cox analyses demonstrated that high disease burden (p = 0.019), prior third-generation EGFR-TKI therapy (p = 0.019), and a poor lung immune prognostic index (LIPI) (p = 0.012) were independent negative predicators of overall PFS and that multiple BMs were negatively correlated with intracranial PFS among patients treated with ICI therapy. Our results suggested that ICI combined with chemotherapy had potent intracranial efficacy and may be a promising treatment candidate in EGFR-mutant NSCLC patients with BMs for whom prior EGFR-TKI therapy failed.
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Project description:Receptor tyrosine kinases (RTKs) play a crucial role in cellular signaling and oncogenic progression. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations, but resistance frequently emerges between 10 to 14 months. A significant factor in this resistance is the role of human EGFR 3 (HER3), an EGFR family member. Despite its significance, effective targeting of HER3 is still developing. This review aims to bridge this gap by deeply examining HER3's pivotal contribution to EGFR TKI resistance and spotlighting emerging HER3-centered therapeutic avenues, including monoclonal antibodies (mAbs), TKIs, and antibody-drug conjugates (ADCs). Preliminary results indicate combining HER3-specific treatments with EGFR TKIs enhances antitumor effects, leading to an increased objective response rate (ORR) and prolonged overall survival (OS) in resistant cases. Embracing HER3-targeting therapies represents a transformative approach against EGFR TKI resistance and emphasizes the importance of further research to optimize patient stratification and understand resistance mechanisms.
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Project description:Background: To determine the clinical activity and safety of Chinese herbal medicine (CHM) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in patients with advanced pulmonary adenocarcinoma (ADC) and the ability of CHM combined with EGFR-TKI to activate EGFR mutations. Methods: Three hundred and fifty-four patients were randomly assigned to EGFR-TKI (erlotinib 150 mg/d, gefitinib 250 mg/d, or icotinib 125 mg tid/d) plus CHM (TKI+CHM, N = 185) or EGFR-TKI plus placebo (TKI+placebo, N = 169). Progression-free survival (PFS) was the primary end point; the secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life [Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)], and safety. Results: The median PFS was significantly longer for the TKI+CHM group (13.50 months; 95% CI, 11.20-16.46 months) than with the EGFR-TKI group (10.94 months; 95% CI, 8.97-12.45 months; hazard ratio, 0.68; 95% CI, 0.51-0.90; P = 0.0064). The subgroup analyses favored TKI+CHM as a first-line treatment (15.97 vs. 10.97 months, P = 0.0447) rather than as a second-line treatment (11.43 vs. 9.23 months, P = 0.0530). Patients with exon 19 deletion had a significantly longer PFS than with 21 L858R. The addition of CHM to TKI significantly improved the ORR (64.32% vs. 52.66%, P = 0.026) and QoL. Drug-related grade 1-2 adverse events were less common with TKI+CHM. Conclusions: TKI+CHM improved PFS when compared with TKI alone in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01745302.
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Project description:BackgroundTyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC). MET amplification drives resistance to EGFR-TKIs in 5-20% of initially sensitive.Egfrmutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment.MethodsTo investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in EGFR-mutated HCC827 cells with MET amplification-mediated erlotinib resistance. These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance.ResultsIn all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1. Furthermore, FGFR1 expression was increased in all MET-TKI resistant cell lines and four out of the six resistant cell lines had increased sensitivity to FGFR inhibition, indicating FGFR1-mediated bypass signaling.ConclusionsEMT is common in the development of sequential EGFR-TKI and MET-TKI resistance in NSCLC cells. Our findings contribute to the evidence of EMT as a common TKI resistance mechanism.
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Project description:BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed.MethodsThe effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed.ResultsThe combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1 were abrogated.ConclusionsThe combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.
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