Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations
Abstract
:1. Introduction
2. Involvement of BRAF in the MAPK Pathway
Regulation of the MAPK Pathway
3. Conferred Resistance Mechanisms in BRAFV600E Tumours
3.1. Resistance Through MAPK Pathway Reactivation
3.2. Resistance Involving Insensitivity to MAPK Regulators
3.3. Other Mechanisms of Resistance
4. Challenges Encountered by Colorectal Cancer (CRC) Patients with BRAFV600E Mutation
Evidence of Specific Resistance Mechanisms in BRAFV600E Mutated CRC
5. Conclusions
Acknowledgments
Conflicts of Interest
Abbreviations
AKT | protein kinase B |
ATP | adenosine triphosphate |
BRAF | v-RAF murine sarcoma viral oncogene homolog B |
CRC | colorectal cancer |
EGFR | epidermal growth factor receptor |
ERK | extracellular signal-regulated kinase |
HSP90 | heat shock protein 90 |
LKB1 | liver kinase B1 |
MAPK | mitogen activated protein kinase |
MEK | mitogen-activated protein kinase kinase |
mTOR | mammalian target of rapamycin |
PCR | polymerase chain reaction |
PTEN | phosphatase and tensin homolog |
RTK | receptor tyrosine kinase |
TSC2 | tuberous sclerosis complex 2 |
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Category | Protein | Effect of ERK Phosphorylation on Its Functions | Reference |
---|---|---|---|
Kinases and phosphatases | MEK1/2 | Either enhances its activity or reduces it depending on the phosphorylation site | [29] |
CRAF | Inhibits its activity | [30,31] | |
BRAF | Inhibits its activity | [32] | |
RSK | Activation and further signal transduction | [33] | |
S6K | Activation | [34,35] | |
DUSPs | Negative feedback loop-indirectly via dephosphorylating ERK1/2 | [36,37,38] | |
SPRYs | Negative feedback loop-directly inactivating upstream | [39,40] | |
Signalling proteins | EGFR | Downregulation of the MAPK pathway | [41] |
Gab2 * | Reduces its activation | [42] | |
SOS * | Negative feedback mechanism via preventing its association with Gab2 | [43] | |
IRS1 * | Impaired its downstream signalling | [44] | |
TSC2 | Weakens its ability to pair with TSC1, therefore Impairs its ability to inhibit mTOR signalling | [45] | |
Cytoskeletal proteins | Crystalline α | Anti-apoptotic protection | [46,47] |
Transcription Factors | ELK * | Transcription of c-Fos | [47,48] |
c-Fos * | Acts as a sensor for ERKs’ signal duration | [49] | |
c-Jun * | Transcription of c-Jun | [50] | |
p53 | Tumour suppressor protein, plays a role in cell cycle | [51,52] | |
c-Myc * | Transcription | [41] | |
Apoptotic proteins | BIM * | Inhibit its pro-apoptotic function | [53] |
Caspase9 | Reduce its pro-apoptotic function | [54] | |
Bad * | Inhibit its pro-apoptotic function | [55] | |
Other proteins | RB * | Cell cycle progression | [56] |
Vif * | Activates HIV-1 replication | [57] |
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Obaid, N.M.; Bedard, K.; Huang, W.-Y. Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations. Int. J. Mol. Sci. 2017, 18, 585. https://doi.org/10.3390/ijms18030585
Obaid NM, Bedard K, Huang W-Y. Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations. International Journal of Molecular Sciences. 2017; 18(3):585. https://doi.org/10.3390/ijms18030585
Chicago/Turabian StyleObaid, Nourah Mohammad, Karen Bedard, and Weei-Yuarn Huang. 2017. "Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations" International Journal of Molecular Sciences 18, no. 3: 585. https://doi.org/10.3390/ijms18030585