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Updated: Apr 28, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models

Luigi Formisano, Lucia Nappi, Roberta Rosa

    Breast Cancer Research : BCR
    |June 3, 2014
    PubMed
    Abstract

    Insights

    Src kinase overactivation drives resistance to HER2 inhibitors in breast cancer. Targeting both EGFR and HER2 with lapatinib reverses this resistance by inhibiting Src-dependent signaling.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Pharmacology

    Background:

    • Src tyrosine kinase overactivation is linked to poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer.
    • Understanding the mechanism of Src-mediated resistance to HER2 inhibitors like lapatinib is crucial for improving treatment outcomes.

    Purpose of the Study:

    • To investigate the role of Src in lapatinib resistance in breast cancer.
    • To identify the signaling pathways through which Src overexpression sustains resistance to lapatinib.

    Main Methods:

    • In vitro studies assessed the effects of Src inhibition on survival, migration, and invasion of lapatinib-resistant breast cancer cells.
    • In vivo experiments utilized JIMT-1 xenografts in nude mice to evaluate the impact of Src inhibition on tumor growth and metastasis.
    • Western blot and ELISA analyses were employed to investigate Src-dependent signal transduction pathways.

    Main Results:

    • Src activation was significantly higher in lapatinib-resistant compared to sensitive cells.
    • The Src inhibitor saracatinib, in combination with lapatinib, synergistically inhibited proliferation, migration, and invasion of resistant cells.
    • Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than HER2 in resistant cells, and combined EGFR/lapatinib treatment counteracted Src-mediated resistance.

    Conclusions:

    • Src activation in lapatinib-resistant breast cancer cells is dependent on EGFR-mediated signaling, not HER2.
    • Combined pharmacologic inhibition of both EGFR and HER2 is necessary to overcome Src-dependent resistance to lapatinib in breast cancer.

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