Do cancer cells have Achilles’ heels?
The answer may lie in a concept called
syntheticlethality that originated
decades ago in studies of fruit flies.
The basic observation is that when fruit
flies carry certain defective genes, they
appear more or less normal, but when
the flies carry a specific combination of
these defective genes, they are not viable.
The interaction of these combinations of
gene defects is called synthetic lethality.
Recently, insights about synthetic
lethality have been applied to cancer
treatments. The hope is that pairs of
synthetic lethal genes can be discovered
in which one of a pair contains a cancer
gene defect and the partner is a non-defective gene. Because a cancer cell
with a defective gene depends on the
non-defective gene partner for survival,
inhibiting the non-defective gene partner
with a drug would kill the cancer cell,
with few side effects expected for normal
cells or tissues. The preference for killing
cancer cells over normal cells would be
attributable to synthetic lethality.
British cancer researcher Alan
Ashworth and his colleagues exploited
synthetic lethality to build better treatments for cancers arising from defective BRCA genes. These defective genes
are seen commonly in breast, ovarian
and prostate cancers. They discovered
that drugs disrupting, or inhibiting, the
function of poly (ADP-ribose) polymer-ases, or PARPs, selectively killed cancer
cells with BRCA gene defects. In other
words, the BRCA and PARP genes are
synthetic lethal pairs.
With this insight, the researchers
pursued clinical trials using PARP
inhibitors to treat patients with cancers
containing defective BRCA genes.
The PARP inhibitor Lynparza (
olapa-rib) was approved by the U.S. Food
and Drug Administration (FDA) in
2014 to treat patients with advanced
ovarian cancer that has BRCA defects.
Additional FDA approvals of PARP
inhibitors for breast and prostate
cancers with BRCA defects have fol-
lowed. PARP inhibitors may also form
synthetic lethal pairs with other defec-
tive cancer genes, including ATM,
ATR, PALB2 and various FANC genes.
In many laboratories, high-tech
functional genomics screens that
analyze the functions and interac-
tions of genes have discovered and
cataloged synthetic lethal gene pairs
in which one of the gene partners
is a defective cancer gene. These
efforts offer a promising avenue to
new cancer treatments. An attractive
feature of this treatment model is that
it can target vulnerabilities in cancer
genes where the defect is loss of func-
tion, like BRCA genes, as well as in
cancer genes where the defect may
create a gain of function, like over-
expression of proteins in M YC and
The concept of synthetic lethality
has yielded new approved drugs to
treat cancers with BRCA gene defects
and is poised to deliver new treatments for other cancers with other
defective genes. Hopefully, all cancer
cells possess vulnerabilities attributable to acquired gene defects so
that, like Achilles’ heel, cancers can
be treated with drugs developed to
exploit these weaknesses.
WILLIAM G. NELSON, MD, PhD, is the director of the Johns Hopkins Kimmel Cancer Center
In Greek mythology, Achilles, the great hero of the Trojan War, was held by the left heel as a baby and immersed in the River Styx by his mother, Thetis, rendering him invulnerable
to all injuries except in the left heel. This weakness was later
exploited by Paris, an otherwise incompetent warrior, to slay
Achilles by aiming an arrow at his heel—the Achilles’ heel.
SYNTHETIC LETHALITY AND CANCER:
Aiming an Arrow
at Achilles’ Heel
PHOTO BY JOE RUBINO