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Resistance of Lung Cancer to Kinase Inhibitors Specific to EGFR or ALK

  • Maicol Mancini
  • Yosef Yarden
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 15)

Abstract

Lung cancer is by far the major cause of cancer-related death. The identification of oncogenic mutations in the genes encoding for the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK) opened the way for development of relatively effective tyrosine kinase inhibitory (TKI) drugs, such as erlotinib and crizotinib, respectively. Unfortunately, resistance to these and other first-generation TKIs evolves in patients within a year or two. Several mechanisms underlie acquired resistance and they include second-site mutations, compensatory signaling pathways and phenotype alterations. Once resolved, mechanisms conferring resistance to TKIs may pave the way for next-generation TKIs, or they may identify combination therapies simultaneously inhibiting the primary and alternative routes to oncogenesis. Herein, we review the first-, second- and third-generation inhibitors of EGFR and ALK, along with the many ways permitting lung cancer cells to evade pharmacological interceptors in experimental systems and in clinical settings.

Keywords

Tumor heterogeneity Kinase domain mutation Acquired resistance Signal transduction Compensatory pathway 

Abbreviations

ALK

Anaplastic lymphoma kinase

CRC

Colorectal cancer

EGFR

Epidermal growth factor receptor

EMT

Epithelia-to-mesenchymal transition

ERK

Extracellular regulated kinase

HER2

Human EGF receptor 2

HGF

Hepatocyte growth factor

mAb

Monoclonal antibody

NSCLC

Non-small cell lung cancer

PI3K

Phosphatidylinositol 3-kinase

RTK

Receptor tyrosine kinase

Notes

Conflict of Interest

No potential conflicts of interest were disclosed.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institut de Recherche en Cancérologie de Montpellier Campus Val d’AurelleMontpellier Cedex 5France
  2. 2.Department of Biological RegulationWeizmann Institute of ScienceRehovotIsrael

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