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Drug Resistance Against Tyrosine Kinase Inhibitor in Gastrointestinal Malignancies

  • L. V. K. S. Bhaskar
  • L. Saikrishna
Chapter

Abstract

Gastrointestinal cancers are heterogeneous and complex among the most common human cancers. In spite of this complexity, certain types of genetic alterations are linked to specific pathological lesions. Genomic and transcriptomic analyses have disclosed molecular subtypes that are characterized by specific genetic aberrations and expression signatures. Identification of better molecular markers to assist detection and prognostic evaluation of the cancer is therefore required. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. Inhibitors of tyrosine kinases (TKIs) have been effectively used for clinical treatment of certain types of cancer. Chronic exposure to gradually increasing concentrations of the TKI over a period of time, cells by activating modified signaling pathway can replace the lack of signal in target therapy, leading to the development of drug resistance. In recent years, researchers have specified different subsets of tyrosine kinase inhibitors’ potential resistance mechanisms in various gastric cancers. This chapter intends to provide an overview of the most recently identified molecular mechanisms of acquired resistance to tyrosine kinase-targeted therapy in various gastrointestinal malignancies.

Keywords

Gastrointestinal cancer Tyrosine kinase inhibitors TKI resistance EGFR VEGF HER2 

Abbreviations

ABC

ATP binding cassette

ATP

Adenosine triphosphate

Bcl-2

B-cell lymphoma 2

bFGF

Basic fibroblast growth factor

CML

Chronic myeloid leukemia

EGFR

Epidermal growth factor receptor

EMT

Epithelial-mesenchymal transition

ErbB2

Epidermal growth factor receptor II (Her 2)

ERK

Extracellular signal-regulated kinase

FGFR

Fibroblast growth factor receptor

FISH

Fluorescent in situ hybridization

FLT3

FMS-like tyrosine kinase 3

FOLFOX

Folinic acid (FA)-fluorouracil (5FU)-oxaliplatin (OX)

GC

Gastric cancer

GI

Gastrointestinal

GOJ

Gastroesophageal junction

HCC

Hepatocellular carcinoma

HGF

Hepatocyte growth factor

hOCT1

Human organic cation transporter type 1

IR

Insulin receptor

JAK

Janus kinase

mAbs

Monoclonal antibodies

mCRC

Metastatic colorectal cancer

MET

Mesenchymal-epithelial transition

mPC

Metastatic pancreatic cancer

nRTKs

Non-receptor tyrosine kinases

OS

Overall survival

PDGFR

Platelet-derived growth factor receptors

PFS

Progression-free survival

PIK3CA

Phosphatidylinositol 3-kinase catalytic subunit

PPARdelta

Peroxisome proliferator-activated receptor delta

PTEN

Phosphatase and TENsin homolog deleted on chromosome 10

RTKs

Receptor tyrosine kinases

TGF-α

Transforming growth factor α

TKI

Tyrosine kinase inhibitor

TKs

Tyrosine kinases

Tm

Melting temperature

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptors

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Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • L. V. K. S. Bhaskar
    • 1
  • L. Saikrishna
    • 2
  1. 1.Sickle Cell Institute ChhattisgarhRaipurIndia
  2. 2.Sri Venkateswara UniversityTirupatiIndia

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