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Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors and Therapeutic Approaches: An Update

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Lung Cancer and Personalized Medicine

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 893))

Abstract

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non small cell lung cancer (NSCLC) is mediated by two major mechanisms namely secondary mutation T790M in EGFR and cMET amplification. Other molecular mediators which contribute towards TKI resistance include the activation of compensatory growth signaling, epithelial mesenchymal transition and microRNAs regulating EGFR and cMET levels. In this chapter, we have included the major mechanisms which contribute towards EGFR TKI resistance in NSCLC. Several therapeutic approaches to overcome TKI resistance are also presented which include second and third generation EGFR TKI inhibitors and cMET inhibitors. Further, the rationale to utilize the combination therapies to simultaneously target EGFR and other major oncogene addictive pathway such as ERBB2 and AXL kinase is outlined. Another promising approach to overcome TKI resistance is to potentiate EGFR protein for degradation. These studies will best be utilized when we can identify the oncogene addictions in an individual patient and tailor the therapy/therapies accordingly for the maximum benefits.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA

    Aarif Ahsan

  2. Bioconjugate Drug Discovery, Oncology Research Unit, Pfizer Inc., 401 N. Middletown Rd., Pearl River, NY, 10965, USA

    Aarif Ahsan

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Correspondence to Aarif Ahsan .

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  1. Wayne State University, Karmanos Cancer Institute, Detroit, Michigan, USA

    Aamir Ahmad

  2. Wayne State University, Karmanos Cancer Institute, Detroit, Michigan, USA

    Shirish Gadgeel

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Ahsan, A. (2016). Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors and Therapeutic Approaches: An Update. In: Ahmad, A., Gadgeel, S. (eds) Lung Cancer and Personalized Medicine. Advances in Experimental Medicine and Biology, vol 893. Springer, Cham. https://doi.org/10.1007/978-3-319-24223-1_7

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