2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

PI3 Kinase in Cancer: From Biology to Clinic
Overview: The discovery and clinical development of smallmolecule
inhibitors of the phosphatidylinositide 3-kinase (PI3
kinase) family of lipid kinases have marked a remarkable
20-year journey that follows the progressive developments in
cancer biology over the last few decades: from hypothesisdriven,
basic cancer research that began with viral oncogenesis
and developed in the 1960s and 70s, through the
discovery of individual mutated oncogenes and tumor suppressor
genes in 1970 and 80s and the linkage of these cancer
genes to signal transduction pathways in the 1990s, to all
large-scale genome-wide sequencing, functional screening,
and network biology efforts today. Thus, PI3 kinase research
began with the discovery in 1985 of a new type of enzyme
activity associated with viral oncogenesis. It benefited greatly
from the discovery of wortmannin and LY294002 as PI3 kinase
THE PI3 kinase family of lipid and protein kinases
regulates an intracellular signaling network that controls
many features of cell behavior, including growth,
survival, motility, metabolism, and additional specialized
functions (Fig. 1). There are four distinct PI3 kinase subfamilies
that are categorized by their substrate specificities,
primary structures, modes of regulation, and domain content.
Of these, the class I isoforms (p110�, �, �, �) and class
IV PI3 kinase-related protein kinase mTOR have been the
most intensively explored as targets for small-molecule
therapeutics. 1-3
The rationale for the development of the class I PI3 kinase
group of lipid kinases is the observation of frequent genetic
and epigenetic alterations that result in activation of the PI3
kinase pathway. 2,3 The class I PI3 kinases catalyze the
addition of a phosphate group to the 3�-hydroxyl position of
the inositide ring present in membrane phosphatidylinositides.
This produces products, the most notable of which is
phosphatidylinositol-3,4,5-trisphosphate (PIP3), which acts
as a second messenger that recruits PKB/AKT to the cell
membrane (Fig. 1). The phosphatase PTEN, a negative
regulator of PI3 kinase signaling that dephosphorylates
PIP3, is one of the most commonly mutated tumorsuppressor
proteins in human malignancy. 4 In contrast, the
gene encoding PIK3CA, the p110� catalytic subunit, is
amplified, overexpressed, and frequently mutated in many
cancers. 5
A greater understanding of the specific and geneticsdependent
roles of the class I isoforms in tumorigenesis
has been established. It has been shown that p110� is
critical for the growth of tumors driven by PIK3CA mutations
and is activated by KRAS and also by receptor tyrosine
kinases that are in turn activated by ligand or by oncogenic
mutation, amplification, or translocation. 2,3 In contrast,
p110� has been identified as the principal isoform mediating
tumorigenesis in PTEN-deficient backgrounds. 6-8 The deltaisoform,
p110�, has also emerged as a potential therapeutic
target for hematological malignancies, notably acute myeloid
leukemia, and perhaps in neuroblastoma, melanoma,
and breast cancers also. 1,2,9,10 Finally, there is potential for
all the class I PI3 kinases to be activated in cancer cells
through mutation of the p85 regulatory subunits that recruit
the catalytic subunit to growth factor receptors.
By Paul Workman, PhD, and Paul Clarke, PhD
inhibitors and chemical tools in late 1980s to mid-90s. Alongside
these tools, genetic validation of PI3 kinase as a target
initially involved activation by upstream oncogenic receptor
tyrosine kinases and RAS mutation, together with overexpression
and amplification of the p110� catalytic isoform of PI3
kinase and frequent loss of the tumor suppressor and negative
regulator of PI3 kinase activity, PTEN. As PI3 kinase drug
development began, further stimulus came from the discovery
through genome sequencing of mutations in PIK3CA, which
encodes p110� and is the most frequently mutated kinase in
the human genome. From these beginnings, there are now
many PI3 kinase inhibitors in clinical trials and more in
preclinical development. We review progress, current challenges,
and future opportunities in this article.
Based on this broad platform of research validation,
inhibition of the class I—and especially the class IA subclass
(p110�, �, �)—has emerged as an important strategy for the
development of novel molecular cancer therapeutics. Looking
further ahead, PI3 kinase inhibitors are anticipated to
have a significant impact on the discovery and development
of new personalized medicines in the oncology setting as well
as finding utility in other disease areas. 10
Discovery of PI3 Kinase Inhibitors
Since the elucidation of the mechanism of action of the
natural product wortmannin and the discovery of the synthetic
flavone LY294002, both of which inhibit the class I
PI3 kinase isoforms and have served as valuable chemical
tools, considerable progress has been made in the design of a
plethora of small-molecule inhibitors. 10-12 High-throughput
screening of compound collections supported by rational
structure-based design combined with medicinal chemistry
optimization has led to the discovery and development of
many chemically diverse inhibitors that possess a range of
PI3 kinase subtype–selectivity profiles.
A number of these inhibitors, such as GDC-0941, GDC-
0980, NVP-BEZ235, NVP-BMK120, GSK-2126458, GSK-
1059615, PF-04691502, XL147, XL765, CAL-101, and
derivatives of wortmannin and LY294002 (as reviewed by
Shuttleworth and colleagues 10 ), have entered early-phase
human trials over recent years and are in some cases
progressing to phase Ib expansion cohort and phase II
single-agent efficacy studies and early combination trials.
A paradigm for the rational discovery and development of
a potent and selective PI3 kinase inhibitor is GDC-0941 that
has a well-defined and informative case-history. 13 In 2007
Hayakawa and colleagues reported the identification of a
pyridofuropyrimidine lead and improved chemical tool com-
From the Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics,
The Institute of Cancer Research, Sutton, Surrey UK.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Paul Workman, PhD, Cancer Research UK Cancer Therapeutics
Unit, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road,
Sutton, Surrey, SM2 5NG UK; email: paul.workman@icr.ac.uk.
© 2012 by American Society of Clinical Oncology.
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