Page 281 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

260 PART III Therapeutic Modalities for the Cancer Patient

Growth
factor
VetBooks.ir Receptor

PIP2 PIP3 PIP2

P P
P P p85 PTEN
p110
AKT
P
P

P P
BAD mTOR

P P
FKHR p27
P P
Inhibition of Cell growth and
apoptosis IKK P GSK3 proliferation
Mdm2
• Fig. 15.7 PI3 kinase signal transduction. After receptor tyrosine kinase activation, PI3 kinase is recruited
to the phosphorylated receptor through binding of the p85 adaptor subunit leading to activation of the
catalytic subunit (p110). This activation results in the generation of the second messenger phosphati-
dylinositol-3,4,5-triphosphate (PIP3). PIP3 recruits AKT to the membrane and after its phosphorylation,
several downstream targets are subsequently phosphorylated leading to either their activation or inhibition.
The cumulative effect results in cell survival, growth, and proliferation. (Reprinted with permission from
Blackwell Publishing, London CA, Vet Comp Oncol 2:177–193, 2004.)

occurs in the BRAF gene (V600E, exon 15) in approximately in canine GISTs. 115–118 There are other well-characterized muta-
60% of human cutaneous melanomas. 87,104,105 This amino acid tions involving RTKs in human cancers including FLT3 ITDs
change causes a conformation change in B-Raf, mimicking its in AML, 119–122 EGFR point mutations in lung carcinomas, 123,124
activated form and thereby inducing constitutive downstream and PI3K-α mutations in several types of carcinomas. 94
ERK signaling and abnormal promotion of cell growth and sur- Overexpression of kinases usually involves the RTKs and
vival. 106,107 RAS is another kinase that is dysregulated through may result in enhanced response of the cancer cells to normal
point mutation in several hematopoietic neoplasms (multiple levels of growth factor; or, if the levels are high enough, the
myeloma, juvenile chronic myelogenous leukemia [CML], acute kinase may become activated through spontaneous dimeriza-
myelogenous leukemia [AML], and chronic myelomonocytic tion in the absence of signal/growth factor. In humans, the RTK
leukemia [CMML]) and in lung cancer, colon cancer, and several HER2 (also known as ErbB2, a member of the EGFR family)
others. 86,108,109 is overexpressed in both breast and ovarian carcinomas and
Another example of a mutation involves KIT, an RTK that this often correlates with a more aggressive phenotype. 125,126,73
normally is expressed on hematopoietic stem cells, melanocytes, in EGFR is also overexpressed in human lung, bladder, cervical,
the central nervous system, and on mast cells. 110 In approximately ovarian, renal, and pancreatic cancers, and some tumors have as
30% of canine grade 2 and grade 3 mast cell tumors (MCTs), many as 60 copies of the gene per cell. 76,127,128 As with HER2,
mutations consisting of ITDs are found in the juxtamembrane such overexpression is linked to a worse outcome in affected
domain of KIT, resulting in constitutive activation in the absence patients. 76
of ligand binding. These mutations are associated with a higher Fusion proteins are generated when a portion of the kinase
risk of local recurrence and metastasis. 111–113 Additional activating becomes attached to another gene through chromosomal rear-
mutations in the extracelluar domain of KIT (specifically exons 8 rangement and the normal mechanisms that control protein func-
and 9) have also been identified in canine MCTs. 114 Interestingly, tion are disrupted. One of the best characterized fusion proteins is
KIT mutations consisting of deletions in the juxtamembrane BCR-ABL, which is found in 90% of patients with CML. 129–132
domain are also found in approximately 50% of human patients ABL is a cytoplasmic TK that, when fused to BCR, results in
with gastrointestinal stromal tumors (GISTs) and are also found dysregulation of ABL, inappropriate activity of the protein, and