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Antitumor Activity of Combination Therapy with Metformin and Trametinib in Non-Small Cell Lung Cancer Cells.

ABSTRACT: Metformin has been widely used as an antidiabetic drug, and reported to inhibit cell proliferation in many cancers including non-small cell lung cancer (NSCLC). In NSCLC cells, metformin suppresses PI3K/AKT/mTOR signaling pathway, but effect of metformin on RAS/ RAF/MEK/ERK signaling pathway is controversial; several studies showed the inhibition of ERK activity, while others demonstrated the activation of ERK in response to metformin exposure. Metformin-induced activation of ERK is therapeutically important, since metformin could enhance cell proliferation through RAS/RAF/MEK/ERK pathway and lead to impairment of its anticancer activity suppressing PI3K/AKT/mTOR pathway, requiring blockade of both signaling pathways for more efficient antitumor effect. The present study tested the combination therapy of metformin and trametinib by monitoring the alterations of regulatory effector proteins of cell signaling pathways and the effect of the combination on cell viability in NCI-H2087 NSCLC cells with NRAS and BRAF mutations. We show that metformin alone blocks PI3K/AKT/mTOR signaling pathway but induces the activation and phosphorylation of ERK. The combination therapy synergistically decreased cell viability in treatment with low doses of two drugs, while it gave antagonistic effect with high doses. These findings suggest that the efficacy of metformin and trametinib combination therapy may depend on the alteration of ERK activity induced by metformin and specific cellular context of cancer cells.

SUBMITTER: Ko E

PROVIDER: S-EPMC7375979 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Antitumor Activity of Combination Therapy with Metformin and Trametinib in Non-Small Cell Lung Cancer Cells.

Ko Eunjeong E Baek Seungjae S Kim Jiwon J Park Deokbae D Lee Youngki Y

Development & reproduction 20200630 2

Metformin has been widely used as an antidiabetic drug, and reported to inhibit cell proliferation in many cancers including non-small cell lung cancer (NSCLC). In NSCLC cells, metformin suppresses PI3K/AKT/mTOR signaling pathway, but effect of metformin on RAS/ RAF/MEK/ERK signaling pathway is controversial; several studies showed the inhibition of ERK activity, while others demonstrated the activation of ERK in response to metformin exposure. Metformin-induced activation of ERK is therapeutica ...[more]

PMID: 32734128

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Project description:BackgroundPatients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF)V600E-mutant non-small cell lung cancer (NSCLC) benefit from treatment with a combination of BRAF and mitogen-activated protein kinase (MEK) inhibitors, but resistance and disease progression develop in most patients. Pre-clinical studies and case studies of melanoma indicate that acquired resistance to BRAF inhibition may be reversible. However, studies on the effects of dabrafenib-trametinib (D/T) re-challenge for relapse in NSCLC are limited.Case descriptionA 58-year-old Chinese woman with a history of smoking and hypertension was diagnosed with stage IV B lung adenocarcinoma with metastasis. The targeted next-generation sequencing (NGS) of the patient's lung tumor biopsy tissues revealed the presence of a BRAF V600E mutation with an allele frequency (AF) of 30.54%. The patient was treated with cytotoxic chemotherapy (the 1st line), D/T targeted therapy (the 2nd line), and immune checkpoint inhibitor monotherapy (pembrolizumab, the 3rd line), all of which achieved a partial response (PR) that lasted for a total of 8 months. The 2nd NGS analysis of the lung tissue specimens revealed the presence of a BRAF V600E mutation (AF =18.41%) without mutations, which was potentially involved in the resistance to BRAF/MEK inhibition. At the 4th line, she subsequently re-challenged D/T, and achieved a 4th PR, lasting for 5 months. The 3rd NGS analysis revealed the retention of the BRAF V600E mutation (AF =0.39%). Her treatment was switched to pembrolizumab (the 5th line), and the disease remained stable for another 6 months as of the last follow-up in November 2021. She didn't experience any adverse events throughout the treatment.ConclusionsOur findings suggest that the re-challenge of D/T and immune checkpoint blockage therapies offer another therapeutic option for NSCLC patients with the BRAF V600E-mutant who have received extensive prior treatments. In addition, our advanced NSCLC patient with the BRAF V600E-mutant also derived long-term clinical benefits from initial chemotherapy, molecular-targeted therapy, and immunotherapy.

Project description:ImportanceUnresected locally advanced non-small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied.ObjectiveTo examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC.Design, setting, and participantsThe Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019.InterventionsPatients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months.Main outcomes and measuresThe primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis.ResultsThe trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event.Conclusions and relevanceIn this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy.Trial registrationClinicalTrials.gov Identifier: NCT02115464.

Dataset Information

Antitumor Activity of Combination Therapy with Metformin and Trametinib in Non-Small Cell Lung Cancer Cells.

Publications

Antitumor Activity of Combination Therapy with Metformin and Trametinib in Non-Small Cell Lung Cancer Cells.

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