Therapeutic strategies for afatinib‐resistant lung cancer harboring <i><scp>HER</scp>2</i> alterations

Torigoe, Hidejiro; Shien, Kazuhiko; Takeda, Tatsuaki; Yoshioka, Takahiro; Namba, Kei; Sato, Hiroki; Suzawa, Ken; Yamamoto, Hiromasa; Soh, Junichi; Sakaguchi, Masakiyo; Tomida, Shuta; Tsukuda, Kazunori; Miyoshi, Shinichiro; Toyooka, Shinichi

doi:10.1111/cas.13571

Cited by 24 publications

(21 citation statements)

References 41 publications

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“…The gene amplification of MET has already been reported as a mechanism of afatinib resistance in lung cancer . AXL upregulation has also been reported as a mechanism of resistance to TKI .…”

Section: Discussionmentioning

confidence: 94%

Acquired resistance mechanisms to afatinib in HER2‐amplified gastric cancer cells

et al. 2019

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Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan‐HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)‐amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2‐amplified gastric cancer cells. Two afatinib‐resistant gastric cancer cell lines were established from 2 HER2‐amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87‐derived resistant cells, whereas it was upregulated in SNU216‐derived resistant cells. In the N87‐derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216‐derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2‐driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance.

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Section: Discussionmentioning

confidence: 94%

Acquired resistance mechanisms to afatinib in HER2‐amplified gastric cancer cells

et al. 2019

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“…Metformin also selectively acts against CSCs by targeting EMT, blocking the IL-6/STAT3 axis or decreasing EMT transcriptional factors, and by increasing tumor sensitivity against other current therapies [197,[283][284][285][286][287]; therefore, it has been included in clinical trials [288]. Furthermore, to overcome the resistance acquired by EMT from EGFRs inhibitors, several studies that combine EGFRs inhibitors with drugs targeting other pathways, such as with FGFRs inhibitors, have been performed [289][290][291][292]. Despite some good results with some drugs against EMT, their toxicity and ability to promote metastasis still remain a concern [222].…”

Section: Clinical Implications and Future Trendsmentioning

confidence: 99%

Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

et al. 2020

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Cancer stem cells (CSCs) represent a tumor subpopulation responsible for tumor metastasis and resistance to chemo- and radiotherapy, ultimately leading to tumor relapse. As a consequence, the detection and eradication of this cell subpopulation represent a current challenge in oncology medicine. CSC phenotype is dependent on the tumor microenvironment (TME), which involves stem and differentiated tumor cells, as well as different cell types, such as mesenchymal stem cells, endothelial cells, fibroblasts and cells of the immune system, in addition to the extracellular matrix (ECM), different in composition to the ECM in healthy tissues. CSCs regulate multiple cancer hallmarks through the interaction with cells and ECM in their environment by secreting extracellular vesicles including exosomes, and soluble factors such as interleukins, cytokines, growth factors and other metabolites to the TME. Through these factors, CSCs generate and activate their own tumor niche by recruiting stromal cells and modulate angiogenesis, metastasis, resistance to antitumor treatments and their own maintenance by the secretion of different factors such as IL-6, VEGF and TGF-ß. Due to the strong influence of the CSC secretome on disease development, the new antitumor therapies focus on targeting these communication networks to eradicate the tumor and prevent metastasis, tumor relapse and drug resistance. This review summarizes for the first time the main components of the CSC secretome and how they mediate different tumor processes. Lastly, the relevance of the CSC secretome in the development of more precise and personalized antitumor therapies is discussed.

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“…We revealed previously that cancer stem cell (CSC)‐like features and epithelial‐to‐mesenchymal transition (EMT) were involved in the resistance of lung cancer to ErbB family‐TKI . Therefore, we also investigated the expression levels of the CSC markers and EMT markers in the resistant cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Clinically, loss of HER2 amplification has been reported after treatment with trastuzumab in patients with breast and gastric cancer . Moreover, there are some reports from vitro studies which suggest downregulated expression of HER2 protein in a neratinib‐resistant breast cancer cell line and a decrease of the copy number of HER2 in an afatinib‐resistant lung cancer cell line . Reduction of HER2 protein expression may be one of the factors contributing to the resistance to HER2 inhibitors, because it results in a decrease in the amount of the drug target.…”

Section: Discussionmentioning

confidence: 99%

“…Human epidermal growth factor receptor 2 was more phos- We revealed previously that cancer stem cell (CSC)-like features and epithelial-to-mesenchymal transition (EMT) were involved in the resistance of lung cancer to ErbB family-TKI. 14,24,25 Therefore, we also investigated the expression levels of the CSC markers and EMT markers in the resistant cell lines. ALDH1A1 is a putative CSC marker, and we found overexpression of ALDH1A1…”

Section: Discussionmentioning

confidence: 99%

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YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

et al. 2020

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Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

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Therapeutic strategies for afatinib‐resistant lung cancer harboring HER2 alterations

Cited by 24 publications

References 41 publications

Acquired resistance mechanisms to afatinib in HER2‐amplified gastric cancer cells

Acquired resistance mechanisms to afatinib in HER2‐amplified gastric cancer cells

Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

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