Epithelial-to-mesenchymal transition (EMT) causing acquired resistance to afatinib in a patient with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma

Poh, Mau Ern; Liam, Chong Kin; Rajadurai, Pathmanathan; Chai, Chee-Shee

doi:10.21037/jtd.2018.06.122

Cited by 23 publications

(17 citation statements)

References 14 publications

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“…EMT is regulated by various signaling mechanisms, including cell surface receptor tyrosine kinases, and the associated interactions are important for its induction [ 22 , 23 ]. Epidermal growth factor receptor (EGFR) is one of the tyrosine kinases related to EMT [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT

Kim

Park

2020

Cancers

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Recently, it has been reported that Fusobacterium nucleatum, a major pathogen involved in chronic periodontitis, may play an important role in colorectal cancer (CRC) progression. In addition, inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease represent major predisposing conditions for the development of CRC, and this subtype of cancer is called colitis-associated cancer (CAC). Although the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. In this study, we investigated the effects of F. nucleatum in experimental colitis induced with dextran sodium sulfate (DSS), which is a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism in both in vitro and in vivo models. F. nucleatum synergistically increased the aggressiveness and epithelial–mesenchymal transition (EMT) characteristics of CRC cells that were treated with DSS compared to those in non-treated CRC cells. The role of F. nucleatum in CAC progression was further confirmed in mouse models, as F. nucleatum was found to significantly increase the malignancy of azoxymethane (AOM)/DSS-induced colon cancer. This promoting effect of F. nucleatum was based on activation of the EGFR signaling pathways, including protein kinase B (AKT) and extracellular signal-regulated kinase (ERK), and epidermal growth factor receptor (EGFR) inhibition significantly reduced the F. nucleatum-induced EMT alteration. In conclusion, F. nucleatum accelerates the progression of CAC by promoting EMT through the EGFR signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT

Kim

Park

2020

Cancers

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“…134 A case report of a 63-year-old female who had never smoked and had been diagnosed with stage IV lung ADC mentioned that EMT was the main culprit for acquired resistance to afatinib. 135 Interesting research demonstrated that NSCLC cells with EMT showed a high level of gefitinib resistance as compared with T790M-harboring NSCLC cells. It was also suggested that an increased level of cancer stem cell (CSC)-like properties may be a factor in the EMT phenotype conferring high resistance to EGFR-TKIs.…”

Section: Pik3ca Mutationmentioning

confidence: 99%

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

Tripathi

Pandey

Rengasamy

et al. 2020

Medicinal Research Reviews

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to a substantial improvement in the prognosis of lung cancer patients by explicitly targeting the activating mutations within the EGFR. Initially, patients harboring tumors with EGFR mutations show progressionfree survival and improvement in the response rates toward all-generation EGFR-TKIs; however, these agents fail to deliver the intended results in the long-term due to drug resistance. Therefore, it is necessary to recognize specific cardinal mechanisms that regulate the resistance phenomenon. Understanding the intricate mechanisms underlying EGFR-TKIs resistance in lung cancer could provide cognizance for more advanced targeted therapeutics. The present review features insights into current updates on the discrete mechanisms, including secondary or tertiary mutations, parallel and downstream signaling pathways, acquiring an epithelial-to-mesenchymal transition (EMT) signature, microRNAs (miRNAs), and epigenetic alterations, which lead to intrinsic and acquired resistance against EGFR-TKIs in lung cancer. In addition, this paper also reviews current possible strategies to overcome this issue using combination treatment of recently developed MET inhibitors, allosteric inhibitors or immunotherapies, transformation of EMT, targeting miRNAs, and epigenetic alterations in intrinsic and acquired EGFR-TKIs resistant lung cancer. In conclusion, multiple factors are responsible for intrinsic and acquired resistance to EGFR-TKIs and understanding of the detailed molecular mechanisms, and recent advancements in pharmacological studies are needed to develop new strategies to overcome intrinsic and acquired EGFR-TKIs resistance in lung cancer.

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“…To our knowledge, this is the first reported case of EMT as the cause of recurrence in a patient with resected stage IIB non‐small‐cell lung carcinoma (NSCLC) after adjuvant chemotherapy. EMT has so far been reported to cause acquired resistance to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors …”

Section: Discussionmentioning

confidence: 99%

Epithelial‐to‐mesenchymal transition (EMT) to sarcoma in recurrent lung adenosquamous carcinoma following adjuvant chemotherapy

et al. 2019

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Adjuvant chemotherapy has long been indicated to extend survival in completely resected stage IB to IIIA non‐small cell lung cancer (NSCLC). However, there is accumulating evidence that chemotherapy or chemoradiotherapy can induce epithelial‐to‐mesenchymal transition (EMT) in disseminated or circulating NSCLC cells. Here, we describe the first case of EMT as the cause of recurrence and metastasis in a patient with resected stage IIB lung adenosquamous carcinoma after adjuvant chemotherapy. We review the literature and explore the possible mechanisms by which EMT occurs in disseminated tumor cells (DTC) or circulating tumor cells (CTC) in response to adjuvant chemotherapy (cisplatin) as a stressor. We also explore the possible therapeutic strategies to reverse EMT in patients with recurrence. In summary, although adjuvant cisplatin‐based chemotherapy in resected NSCLC does extend survival, it may lead to the adverse phenomenon of EMT in disseminated tumor cells (DTC) or circulating tumor cells (CTC) causing recurrence and metastasis.

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Epithelial-to-mesenchymal transition (EMT) causing acquired resistance to afatinib in a patient with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma

Cited by 23 publications

References 14 publications

Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT

Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

Epithelial‐to‐mesenchymal transition (EMT) to sarcoma in recurrent lung adenosquamous carcinoma following adjuvant chemotherapy

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