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nrc.2017.98

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RESEARCH HIGHLIGHTS
Nature Reviews Cancer | Published online 25 Oct 2017; doi:10.1038/nrc.2017.98
TA R G E T E D T H E R A P I E S
Carl Conway/Macmillan
Publishers Limited
the ERK2
pathway
mediates drug
addiction in
cancer cells
Understanding tumour drug addiction
Tumour cells with acquired
resistance to targeted agents can
develop a dependency on these
drugs for survival, exposing potential
therapeutic vulnerabilities. Kong
et al. now provide insight into the
previously uncharacterized mechanisms that underly ‘drug addiction’ in
melanoma cells.
To model drug addiction,
BRAFV600E melanoma cell lines
were treated for 3–5 months with a
BRAF inhibitor (BRAFi), alone or in
combination with a MEK inhibitor
(MEKi), after which cell populations
emerged with acquired resistance to
BRAFi or BRAFi/MEKi; expectedly,
drug-resistant cells underwent
massive cell death upon acute drug
withdrawal. To functionally identify
the genes responsible for drug addiction, a genome-wide CRISPR–Cas9
knockout screen was employed;
following drug withdrawal in
drug-addicted cells, clones
emerged that had lost the drug
addiction phenotype
and harboured
knockout
of either
MAPK1 (which encodes ERK2),
JUNB, MAP2K1 (which encodes
MEK1) or FOSL1 (which encodes
FRA1). Genetic ablation of MAPK1,
JUNB or FOSL1, but not MAPK3
(which encodes ERK1), prevented
drug withdrawal-induced cell
death in melanoma cell lines and
melanoma xenograft mouse models,
suggesting a role for the ERK2–
JUNB–FRA1 pathway in drug addiction and illustrating a mechanistic
specificity for ERK2 over ERK1.
Indeed, treatment discontinuation
hyperactivated MEK–ERK signalling
in drug-resistant cells, and low-dose
ERK inhibitor treatment prevented
cell death following drug withdrawal.
The authors next investigated
whether transcriptional reprogramming mediated drug addiction.
RNA profiling in drug-addicted
cells after treatment cessation but
before cell death revealed a major
gene expression switch involving
decreased expression of proliferation
genes and elevated expression of
cell invasion genes, suggesting a
phenotypic switch reminiscent of
epithelial-to-mesenchymal transition
(EMT). Moreover, strong downregulation of microphthalmia-associated
transcription factor (MITF) — a regulator of melanocyte cell lineage and
EMT — and enrichment of AP-1,
TEAD and JUNB transcriptional
signatures were reported after drug
discontinuation. Conversely, expression of JUNB, FRA1 and the receptor
tyrosine kinase AXL was induced
by drug withdrawal. Importantly,
upregulation of fibronectin,
downregulation of E-cadherin
and enhanced migratory capacity
in vitro — hallmarks of EMT — were
observed following drug withdrawal.
This phenotypic switch was
dependent on ERK2, JUNB and
MITF in melanoma cells and xeno­
graft models, and restoration of
MITF expression in drug-addicted
cells before treatment withdrawal
markedly protected cells from death.
Importantly, treatment with dacarbazine after withdrawal of BRAFi treatment in drug-addicted cells markedly
enhanced the cytotoxic effects of
drug withdrawal, demonstrating
a potential alternating therapeutic
strategy. Intriguingly, addiction to
epidermal growth factor receptor
(EGFR) inhibitors was also mediated
by an ERK2-dependent invasive
phenotype switch in non-small-cell
lung cancer cells, suggesting that
this mechanism is also associated
with MAPK-targeted drugs in other
tumour types.
Overall, the study reveals that
the ERK2 pathway mediates drug
addiction in cancer cells. These
findings might help to inform clinical
strategies that employ alternating
drug treatments — for example,
drug withdrawal followed by DNA
damage-inducing therapy — as
opposed to ‘drug holiday’ approaches,
to harness the phenomenon of
drug addiction.
NATURE REVIEWS | CANCER
Conor A. Bradley
ORIGINAL ARTICLE Kong, X. et al. Cancer drug
addiction is relayed by an ERK2-dependent
phenotype switch. Nature http://dx.doi.org/
10.1038/nature24037 (2017)
www.nature.com/nrc
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