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Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells.

ABSTRACT: Although non-small cell lung cancer (NSCLC) patients with EGFR mutation positive (EGFR M+) tumors initially respond well to EGFR tyrosine kinase inhibitor (TKI) monotherapy, the responses are usually incomplete. In this study we show that AKT inhibition, most importantly AKT2 inhibition, synergises with EGFR TKI inhibition to increase cell killing in EGFR M+ NSCLC cells. However, our data also suggest that the synergistic pro-apoptotic effects may be stunted due to a prosurvival autophagy response induced by AKT inhibition. Consequently, inhibiting autophagy with chloroquine significantly enhanced tumor cell death induced by gefitinib and AKT inhibitors in EGFR M+ cells in vitro, and produced greater tumor shrinkage in EGFR M+ xenografts in vivo. Together, our findings suggest that adding chloroquine to EGFR and AKT inhibition has the potential to improve tumor responses in EGFR M+ NSCLC, and that selective targeting of AKT2 may provide a new treatment option in NSCLC.

SUBMITTER: Bokobza SM

PROVIDER: S-EPMC4148097 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells.

Bokobza Sivan M SM Jiang Yanyan Y Weber Anika M AM Devery Aoife M AM Ryan Anderson J AJ

Oncotarget 20140701 13

Although non-small cell lung cancer (NSCLC) patients with EGFR mutation positive (EGFR M+) tumors initially respond well to EGFR tyrosine kinase inhibitor (TKI) monotherapy, the responses are usually incomplete. In this study we show that AKT inhibition, most importantly AKT2 inhibition, synergises with EGFR TKI inhibition to increase cell killing in EGFR M+ NSCLC cells. However, our data also suggest that the synergistic pro-apoptotic effects may be stunted due to a prosurvival autophagy respon ...[more]

PMID: 24946858

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Project description:BackgroundThis study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs).MethodsWe retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test.ResultsA total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group.ConclusionNSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

Project description:Background and objectiveMutations located in epidermal growth factor receptor (EGFR) tyrosine kinase domains have been described as the 'Achilles heel' of non-small cell lung cancer (NSCLC) and can be targeted by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the clinical benefits of EGFR-TKIs are limited, and drug resistance inevitably occurs in NSCLC patients after long-term exposure to certain drugs. EGFR-TKI combination therapies, including combined targeted therapy, radiotherapy, chemotherapy, and immunotherapy, have shown promise in addressing this issue. This literature review analyzed the rationale and controversies of clinical research related to various EGFR-TKI combination therapies.MethodsThe PubMed database was searched to retrieve articles published from January 1, 2001 to April 15, 2023 using the following Medical Subject Headings (MeSH) terms: "EGFR-mutated non-small cell lung cancer" and "clinical trial". Google Scholar was also reviewed to retrieve additional articles. The search was limited to articles published in English.Key content and findingsIn this review, we summarized EGFR-TKI combination therapies, including combined targeted therapy, radiotherapy, chemotherapy, and immunotherapy, most of which have shown efficacy and safety in patients with EGFR-mutated NSCLC. A number of clinical studies with large sample sizes have analyzed the activity and toxicity of combined therapies and explored potential and well-tolerated treatment options.ConclusionsEGFR mutations have been detected in many NSCLC patients and can be targeted by EGFR-TKIs. However, drug resistance after long-term exposure remains a significant challenge for this type of treatment. Most clinical trials have shown that the combination of EGFR-TKIs and targeted therapy, chemotherapy, radiotherapy or immunotherapy is efficacious and safe in the treatment of EGFR-mutated NSCLC. It should be noted that in some instances, serious adverse events have led to the termination of trials. However, EGFR-TKI combination therapy is indeed an effective approach for the treatment of patients with EGFR-mutated NSCLC and deserves further development.

Dataset Information

Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells.

Publications

Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells.

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