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C.J.L. acknowledges funding from Breast Cancer Now, Cancer
Research UK, and National Health Service funding to the National
Institute for Health Research Royal Marsden Hospital Biomedical
Research Centre. A.A. is funded by Susan G. Komen for the Cure,
The Breast Cancer Research Foundation, The BRCA Foundation,
and UCSF. We thank D. Krastev (ICR, London) for assistance with
figure generation and A. Tutt (ICR, London and King’s College
London) for helpful suggestions. A.A. is on the Scientific Advisory
Board of Genentech and is a paid consultant for AtlasMDX,
Third Rock Ventures, Pfizer, and Merck Serono. A.A. is a
cofounder of Tango Therapeutics. C.J.L. is a paid consultant for
AstraZeneca, Tango Therapeutics, and Sun Pharma. In accord with
the Institute of Cancer Research Rewards to Inventors Scheme,
A.A. is named as an inventor on patents describing the use of PARP
inhibitors for the treatment of cancer [WO2014013231 (A1) no.
2014-01-23, US2012135983 (A1) no. 2012-05-31, US2012010204 (A1)
no. 2012-01-12, US2006142231 (A1) no. 2006-06-29, and WO2008020180
(A2) no. 2008-02-21]. In accord with the Institute of Cancer
Research Rewards to Inventors Scheme, C.J.L. is named as an
inventor on patents describing the use of PARP inhibitors for the
treatment of cancer [WO2014013231 (A1) no. 2014-01-23 and
WO2008020180 (A2) no. 2008-02-21].
Drugging RAS: Know the enemy
Bjoern Papke and Channing J. Der*
The three RAS oncogenes make up the most frequently mutated gene family in human
cancer. The well-validated role of mutationally activated RAS genes in driving cancer
development and growth has stimulated comprehensive efforts to develop therapeutic
strategies to block mutant RAS function for cancer treatment. Disappointingly, despite more
than three decades of research effort, clinically effective anti-RAS therapies have remained
elusive, prompting a perception that RAS may be undruggable. However, with a greater
appreciation of the complexities of RAS that thwarted past efforts, and armed with new
technologies and directions, the field is experiencing renewed excitement that mutant
RAS may finally be conquered. Here we summarize where these efforts stand.
RAS genes have the distinct honor of being the first mutated genes identified in hu- man cancer, ushering in the era of molec- ularly targeted anticancer drug discovery. Although our roster of cancer genes now
exceeds 600 (COSMIC v80; http://cancer.sanger.
ac.uk/cosmic), the three RAS genes constitute
the most frequently mutated oncogene family in
cancer, with RAS mutations found in ~25% of
human tumors. Despite more than 30 years of
intensive efforts to develop pharmacologic inhibitors of RAS, a clinically effective anti-RAS
therapy remains elusive (1–3). The history of anti-RAS drug discovery is marked by mistakes,
missteps, and misconceptions. As the military
strategist General Sun Tzu wrote in the Art of
War, “If you know neither the enemy nor yourself, you will succumb in every battle.” With the
establishment of the RAS Initiative in 2013, the
U.S. National Cancer Institute proclaimed a new
war on RAS (4). Although our knowledge of RAS
remains far from complete, there is a sense that
the time is finally at hand to drug a protein once
considered undruggable. In this Review, we provide an update and a perspective on current strategies to make anti-RAS therapies a reality (Fig. 1).
Aberrant RAS function in cancer
The three human RAS genes are not mutated at
equivalent frequencies in cancer. KRAS is the most
frequently mutated (85% of all RAS-driven cancers), followed by NRAS (12%) and HRAS (3%)
(COSMIC v80). RAS mutations are most common in
the top three cancers responsible for cancer deaths
in the United States: pancreatic ductal adenocarcinomas (PDACs; 95%), colorectal adenocarcinomas (CRCs; 52%) and lung adenocarcinomas (LACs;
31%) (1–3). In contrast, RAS mutations are found
rarely (<2%) in breast, ovarian, and brain cancers.
KRAS is the predominant isoform mutated in
PDACs, CRCs, and LACs. NRAS is the predom-
inant isoform mutated in cutaneous melanomas
and acute myelogenous leukemia, whereas HRAS
is the predominant isoform mutated in bladder
and head and neck squamous cell carcinomas
(1). Why KRAS is preferentially mutated overall,
and why a particular RAS gene is preferentially
mutated in specific cancers, are questions that
remain to be fully answered.
Early failures in RAS drug discovery
Early approaches considered for developing RAS
inhibitors were guided by understanding the biochemical defects of mutant RAS proteins (5). The
three RAS genes encode four closely related small
guanosine triphosphatases (GTPases, enzymes
that hydrolyze guanosine triphosphate): HRAS,
KRAS4A, KRAS4B, and NRAS. Driven by the convenience of available reagents (expression vectors
and antibodies), much of the current knowledge
of RAS is based largely on earlier studies centered
on HRAS. The unsuccessful attempts to develop
farnesyltransferase inhibitors (FTIs) as anti-RAS
drugs (see below) resulted from the misconception that the four RAS proteins were identical in
function. With an ever-growing appreciation that
different RAS proteins will have distinct roles in
cancer, the field has now shifted its focus to KRAS,
the isoform most frequently mutated in cancer,
and the predominant splice variant, KRAS4B (6).
RAS proteins function as molecular switches
that regulate a diversity of cytoplasmic signal
transduction networks (2). RAS can exist in two
states: the guanosine diphosphate (GDP)–bound
“off” state and the GTP-bound “on” state. Active
RAS-GTP binds to a spectrum of catalytically diverse downstream effectors. The RAS GDP-GTP
cycle is regulated by guanine nucleotide exchange
factors (GEFs; e.g., SOS1) that promote nucleotide exchange and formation of RAS-GTP.
GTPase-activating proteins (GAPs; e.g., neuro-fibromin) stimulate the hydrolysis of the bound
GTP, forming inactive RAS-GDP (7).
Cancer-associated RAS genes harbor missense mutations that produce single amino acid
substitutions primarily at codons 12, 13, or 61.
These mutations impair intrinsic and GAP-stimulated GTP hydrolysis rates and/or increase
intrinsic exchange rates, favoring stimulus-independent formation of active RAS-GTP. Thus,
the earliest ideas centered on developing small-molecule antagonists of GTP binding. However,
the picomolar affinity of RAS for GTP and the mil-limolar cellular concentrations of GTP rendered
Lineberger Comprehensive Cancer Center, University of
North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
*Corresponding author. Email: firstname.lastname@example.org
FRONTIERS IN CANCER THERAPY