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Review
. 2020 Mar 20;12(3):731.
doi: 10.3390/cancers12030731.

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

Charles Pottier  1   2 , Margaux Fresnais  3   4 , Marie Gilon  1 , Guy Jérusalem  2 , Rémi Longuespée  3 , Nor Eddine Sounni  1
Affiliations
Review

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

Charles Pottier et al. Cancers (Basel). .

Abstract

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects.

Keywords: cancer; oncology; pharmacology; tyrosine kinase inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Activation of tyrosine kinase receptor. Ligand binding stabilizes connections between monomeric receptors to form an active dimer, which in turn activates the intracellular kinase. Three main effectors can be activated later: phosphoinositide 3-kinase (Pi3K), rat sarcoma (RAS), and phospholipase C (PLC).
Figure 2
Figure 2
Receptor tyrosine kinase (RTK) network modeling proposed by the Kitano’s “bow tie”. The set of RTKs (input layer) influences a small number of intermediaries, such as mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (Pi3K), and Ca2+ signaling (core processes), which leads to the activation of a complex signaling network implicating Pi3K/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), rat sarcoma (RAS)/MAPK, Janus kinase (JAK)/STAT, and phospholipase C (PLC)/Ca2+/calmodulin-dependent protein kinase-protein kinase C (CaMK-PKC) pathways with their numerous crosstalks. The result of the signaling cascade leads to a transcriptional control.
Figure 3
Figure 3
Time line of receptor tyrosine kinase inhibitor (RTKI) development and approval for the treatment of cancer.
See this image and copyright information in PMC

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