tance in a murine model of an aggressive
type of acute lymphoblastic leukemia
(ALL) called Philadelphia chromo-
some–positive ALL.^1 This cancer is
characterized by the fusion of two genes,
BCR and ABL1, and is often treated
with high doses of small-molecule
drugs that inhibit the resulting BCR-
ABL1 oncoprotein.
Blasting ALL cells in vitro with
dasatinib or bosutinib, two common
BCR-ABL1 inhibitors, resulted in the
emergence of resistance to both drugs,
regardless of which compound the cells
were exposed to, the researchers found.
But drug screening revealed that these
resistant cells showed increased vul-
nerability, or “collateral sensitivity,” to
a selection of other drugs. Sequencing
assays revealed a single base mutation,
a guanine-to-cytosine substitution, in
ABL1 that appeared to be responsible
both for protection against dasatinib
and bosutinib and for sensitivity to at
least four other small-molecule drugs—
a weakness that, the researchers write
in their paper, should be “therapeuti-
cally exploitable.”
More recently, Sottoriva and col-
leagues applied a similar approach to
manipulate the evolution of non-small
cell lung cancer (NSCLC) cells in vitro.^2
The researchers first bombarded their
cell lines with trametinib, which, as
expected, caused major cell death fol-
lowed by the growth of drug-resistant
cells a few weeks later. Sequencing
revealed that these trametinib-resistant
cell lines had all lost functional copies of
the gene coding for CDKN2A, a protein
that helps regulate cyclin-dependent
kinases (CDK) and, consequently, cell
division. Because the loss of CDKN2A
is known to lead to increased produc-
tion of certain CDKs, the team predicted
that the cells would be particularly sen-
sitive to CDK inhibitors. Sure enough,
such drugs proved twice as lethal in the
trametinib-evolved lines as in control
NSCLC cells.
Efforts to target collateral sensitiv-
ity bring their own challenges, however.
For starters, collateral sensitivity may
be relatively rare, or at least difficult
to identify. In their study, Sottoriva
and colleagues described a second set
of NSCLC lines, this time treated with
gefitinib, which targets another protein
involved in cell signaling called epider-
mal growth factor receptor (EGFR).The cells duly gained gefitinib resis-
tance, but they didn’t show collateral
sensitivity to any of the nearly 500 other
drugs the team hit them with, including
several that the researchers identified
as good candidates based on genetic
sequencing of resistant cell lines.
Even when researchers can iden-
tify collateral sensitivity, work by sev-
eral groups suggests that it often arises
unpredictably and may be tempo-
ra r y. Tumors continue to diversify as
cells replicate and accumulate muta-
tions, so cancers may eventually evolve
resistance to both the original treat-
ment and the therapy designed to take
advantage of resulting collateral sen-
sitivities. Charles Swanton, a clinician
scientist at the Francis Crick Institute
and University College London, notes
that in lung cancer, for example, tumor
sequencing data suggest that evolution
becomes “less constrained, not more
constrained” as cancer progresses. “In
terms of forcing tumors down cul-
de-sacs, I think perhaps in very early
stages of disease that might be a fruit-
ful approach,” he says. “But I think in
later stages of disease, the tumor is too
diverse for that to be possible.”TRACKING CHANGES
To effectively manipulate a tumor’s evolution, researchers need a way of monitoring the various subpopulations of
cancer cells within that tumor. Standard tissue biopsies are impractical for many cancer types and tend to provide
poor measures of tumor heterogeneity: one study of renal carcinoma patients found that a single biopsy identified
on average just a little more than half of the mutations in each tumor (NEJM, 366:883–92, 2012). Many researchers
have consequently switched their attention to liquid biopsies, which pick up cancer-related biomarkers circulating in the
blood and may prove to be cheaper, less-invasive, and more-effective ways of monitoring within-tumor changes over time.
A proof-of-concept study by a team at Institut Curie in France a couple of years ago used whole-exome sequencing analyses
of circulating DNA to detect the rise of tumor subpopulations resistant to chemotherapy in 19 patients with neuroblastoma tumors
(Clin Cancer Res, 24:939–49, 2018), while a team at Asahikawa Medical University in Japan did the same with non-small cell lung
cancer patients receiving tyrosine kinase inhibitors (BMC Cancer, 18:1136, 2018). One analysis published last year found that, in nearly
80 percent of cases, this approach identified clinically relevant, resistance-inducing mutations that had been missed by tissue biopsies,
raising researchers’ hopes that the technique could be effective for monitoring tumor evolution (Nat Med, 25:1415–21, 2019). Other types of
liquid biopsies include analyses of circulating tumor cells and of genetic material (usually RNAs) in tumor-derived extracellular vesicles.
These approaches are being evaluated in multiple clinical trials as a way to monitor patient responses to cancer therapies, but it will be a while
before they’re ready for use in long-term, evolution-focused treatments, says Robert Gatenby of the Moffitt Cancer Center. Researchers don’t know,
for example, if the proportions of various types of circulating DNA directly mirror the proportions of each tumor subpopulation, or whether they “rep-
resent disproportionately the populations that are losing—or the populations that are winning—the evolutionary battles,” he says. “We’re hoping
[these techniques] will help us, but there’s a lot of work that has to be done.”