Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

Chen, Hengyi; Lin, Caiyu; Peng, Tao; Hu, Cheng; Lu, Conghua; Li, Li; Wang, Yübo; Han, Rui; Mao, Feng; Sun, Fenfen; He, Yong

doi:10.1038/s41419-020-2307-5

Cited by 20 publications

(16 citation statements)

References 37 publications

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“…The antidiabetic drug metformin combined with alectinib overcomes HGF/Met-induced alectinib resistance by blocking the complex formation between MET and Gab1, thus inhibiting Gab1 phosphorylation and activating the downstream signaling pathway. These results suggest that metformin combined with alectinib may help overcome alectinib resistance caused by the HGF/MET signaling pathway activation, improving the efficacy of alectinib (77). Cerivastatin, a rate-limiting enzyme inhibitor of the mevalonate pathway, showed anticancer activity against ALK-TKI in vitro and in vivo, accompanied by inactivation of the transcription-assisted regulator YAP.…”

Section: Activation Of Bypass Signaling Pathwaysmentioning

confidence: 91%

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

et al. 2021

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Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.

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Section: Activation Of Bypass Signaling Pathwaysmentioning

confidence: 91%

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

et al. 2021

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“…Blocking the action of HGF receptor would help in enhancing the sensitivity of cancer to tyrosine kinase inhibitors. Therefore combination therapy with metformin might be useful [4]. A drug that inhibits the production of HGF would also make cancer more sensitive to treatment.…”

Section: Discussionmentioning

confidence: 99%

Understanding the Evolutionary Games in NSCLC Microenvironment

Bhattacharya

Velde

Marusyk

et al. 2020

Preprint

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While initially highly successful, targeted therapies eventually fail as populations of tumor cells evolve mechanisms of resistance, leading to resumption of tumor growth. Historically, cell-intrinsic mutational changes have been the major focus of experimental and clinical studies to decipher origins of therapy resistance. While the importance of these mutational changes is undeniable, a growing body of evidence suggests that non-cell autonomous interactions between sub-populations of tumor cells, as well as with non-tumor cells within tumor microenvironment, might have a profound impact on both short term sensitivity of cancer cells to therapies, as well as on the evolutionary dynamics of emergent resistance. In contrast to well established tools to interrogate the functional impact of cell-intrinsic mutational changes, methodologies to understand non-cell autonomous interactions are largely lacking.Evolutionary Game Theory (EGT) is one of the main frameworks to understand the dynamics that drive frequency changes in interacting competing populations with different phenotypic strategies. However, despite a few notable exceptions, the use of EGT to understand evolutionary dynamics in the context of evolving tumors has been largely confined to theoretical studies. In order to apply EGT towards advancing our understanding of evolving tumor populations, we decided to focus on the context of the emergence of resistance to targeted therapies, directed against EML4-ALK fusion gene in lung cancers, as clinical responses to ALK inhibitors represent a poster child of limitations, posed by evolving resistance. To this end, we have examined competitive dynamics between differentially labelled therapy-naïve tumor cells, cells with cell-intrinsic resistance mechanisms, and cells with cell-extrinsic resistance, mediated by paracrine action of hepatocyte growth factor (HGF), within in vitro game assays in the presence or absence of front-line ALK inhibitor alectinib. We found that producers of HGF were the fittest in every pairwise game, while also supporting the proliferation of therapy-naïve cells. Both selective advantage of these producer cells and their impact on total population growth was a linearly increasing function of the initial frequency of producers until eventually reaching a plateau. Resistant cells did not significantly interact with the other two phenotypes. These results provide insights on reconciling selection driven emergence of subpopulations with cell non-cell autonomous resistance mechanisms, with lack of evidence of clonal dominance of these subpopulations. Further, our studies elucidate mechanisms for co-existence of multiple resistance strategies within evolving tumors. This manuscript serves as a technical report and will be followed up with a research paper in a different journal.

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“…The HGF-MET axis is now recognized as playing a vital role in driving VEGF inhibitor resistance [45]. HGF and its physiological receptor tyrosine kinase MET have been reported to be involved in acquired resistance to various tyrosine kinase inhibitors and have been proposed as critical targets in cancer therapy [46]. IP-10 (CXCL10) is an interferon-inducible cytokine that is efficiently induced by IFNβ.…”

Section: Discussionmentioning

confidence: 99%

Synergistic enhancement of efficacy of platinum drugs with verteporfin in ovarian cancer cells

2020

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Background: Epithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells. Methods: The efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array. Results: Treatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment. Conclusions: Either in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients.

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Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

Cited by 20 publications

References 37 publications

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Understanding the Evolutionary Games in NSCLC Microenvironment

Synergistic enhancement of efficacy of platinum drugs with verteporfin in ovarian cancer cells

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