JBC Reviews
New strategies for targeting kinase networks in cancer

https://doi.org/10.1016/j.jbc.2021.101128Get rights and content
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Targeted strategies against specific driver molecules of cancer have brought about many advances in cancer treatment since the early success of the first small-molecule inhibitor Gleevec. Today, there are a multitude of targeted therapies approved by the Food and Drug Administration for the treatment of cancer. However, the initial efficacy of virtually every targeted treatment is often reversed by tumor resistance to the inhibitor through acquisition of new mutations in the target molecule, or reprogramming of the epigenome, transcriptome, or kinome of the tumor cells. At the core of this clinical problem lies the assumption that targeted treatments will only be efficacious if the inhibitors are used at their maximum tolerated doses. Such aggressive regimens create strong selective pressure on the evolutionary progression of the tumor, resulting in resistant cells. High-dose single agent treatments activate alternative mechanisms that bypass the inhibitor, while high-dose combinatorial treatments suffer from increased toxicity resulting in treatment cessation. Although there is an arsenal of targeted agents being tested clinically and preclinically, identifying the most effective combination treatment plan remains a challenge. In this review, we discuss novel targeted strategies with an emphasis on the recent cross-disciplinary studies demonstrating that it is possible to achieve antitumor efficacy without increasing toxicity by adopting low-dose multitarget approaches to treatment of cancer and metastasis.

Keywords

cancer therapy
receptor tyrosine kinases
mitogen-activated protein kinase (MAPK)
drug resistance
cell signaling
combination therapy
targeted therapy
inhibitor
mathematical modeling
kinase network

Abbreviations

ABL1
Abelson tyrosine-protein kinase 1
ALK
anaplastic lymphoma kinase
BCL2
B-cell lymphoma 2
BCR
breakpoint cluster region
BRD4
bromodomain-containing protein
4CML
chronic myelogenous leukemia
DDR1
discoidin domain receptor tyrosine kinase 1
EGFR
epidermal growth factor receptor
GIST
gastrointestinal stromal tumor
HER2
human epidermal growth factor receptor 2
IGF1R
insulin-like growth factor 1 receptor
JAK/STAT
janus kinase/signal transducer and activator of transcription
MIB-MS
multiplexed inhibitor beads coupled with mass spectrometry
MEK/ERK
mitogen-activated kinase kinase/extracellular signal regulated kinase
mTOR
mammalian target of rapamycin
PD1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PI3K/AKT
phosphoinositide 3-kinase/protein kinase B
RKIP
Raf kinase inhibitory protein
TNBC
triple-negative breast cancer

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