2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

PI3 KINASE IN CANCER
Fig. 1. The PI3 kinase network. Class I PI3 kinases are activated to varying extents by receptor tyrosine kinases (RTKs) and G-protein coupled
receptors (GPCRs). PI3 kinases phosphorylate the 3�-hydroxy position of inositol ring of phosphatidylinositides, yielding lipid products that
include phosphatidylinositol-3,4,5-trisphosphate (PIP3), generated from phosphatidylinositol-4,5-bisphosphate (PIP2). PIP3 is a second messenger
molecule that recruits certain protein kinases with PH domains, such as PDK1 and AKT, to the cell membrane (dashed line), resulting in
their activation and stimulation of the PI3 kinase signaling network. PI3 kinase may promote cancer through both AKT-dependent and
AKT-independent mechanisms, the latter via PDK1 and the serine/threonine-protein kinase 3 (SGK3). 31 Activation of the PI3 kinase pathway is
very common in a wide range of cancers. PIK3CA, which encodes the p110� catalytic subunit of PI3 kinase, appears to be the most commonly
mutated kinase in the entire human cancer genome (12% of all cancers) and is also amplified in some tumors. PTEN, which encodes the opposing
phosphatase to PI3 kinase, is the second most commonly affected tumor-suppressor gene after p53. 32 Activation of PI3 kinase-signaling in
cancer also occurs as a result of mutation or increased expression of RTKs, AKT, and RAS. Activation of PI3 kinase signaling has been shown to
reduce cellular dependence on growth factors, attenuate apoptosis, and facilitate tumor growth and invasiveness. Class I PI3 kinases are shown
here as molecular targets of PI3 kinase inhibitors. Figure adapted with permission from Clarke and Workman. © 2012 American Society of
Clinical Oncology. All rights reserved. 22
use of proof-of-mechanism pharmacodynamic biomarkers to
demonstrate target and pathway modulation in both the
preclinical discovery phase and the early clinical development
of PI3 kinase inhibitors is crucial for the implementation
of the PhaT. 21 This enables rational optimization of
dose and schedule of administration as well as go/no-go
decision making. 23 Available proof-of-mechanism biomarkers
of signaling output, such as phosphorylation of ribosomal
protein S6, PRAS40, 4EBP1, and AKT have been used as
indicators of PI3 kinase-pathway inhibition in both tumor
and surrogate tissues and certainly appear to be fit for
purpose. 10
In contrast, we do not yet have biomarkers that are
robustly predictive for sensitivity and resistance in the
clinic. Several nonclinical studies have defined intrinsic
factors such as HER2 amplification, PIK3CA mutations, or
combined defects in these genes as factors that may influence
the sensitivity of breast tumors to PI3 kinase inhibitors.
10 On the other hand, the presence of a KRAS mutation
may be a dominant determinant of resistance in other types
of cancer. 10,13 The currently available therapeutic response
biomarkers are probably best viewed as enrichment biomarkers,
which can be used in early clinical trials for
selecting patients with tumors having molecular characteristics
that make them somewhat more likely to respond.
It is clear that much more work needs to be done to
identify, validate, and clinically qualify biomarkers that
may be truly predictive. Additional biomarkers may well be
needed for drugs with different PI3 kinase-selectivity profiles.
For example, tumor cells harboring activating mutations
in the PIK3CA gene are potentially dependent on or
“addicted to” this isoform, whereas cancer cells deficient in
PTEN expression can exhibit a dependency on p110�. 1
As a further complication, it should also be considered
that in addition to their direct therapeutic action on cancer
cells, PI3 kinase inhibitors can exert effects on tumor angiogenesis,
immune cells, and other tumor microenvironmental
interactions. Hence, it is quite conceivable that there may
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