Triple negative breast cancer is harder to treat than other types of
breast cancer because, as its name suggests, it lacks three receptors
that usually serve as targets for anti-cancer drugs. Treatment options
are therefore limited to standard chemotherapy, which in many cases
A promising new combination therapy for a particularly aggressive
form of breast cancer has been identified by Weizmann Institute
scientists, as was recently reported in Cancer Research
potential dual-acting therapeutic strategy not only inhibits tumor
growth and survival but also circumvents the problem of drug-induced
‘The new dual-acting therapeutic strategy inhibits tumor growth and survival and also circumvents the problem of drug-induced resistance.’
In their study, Prof. Sima Lev, postdoctoral fellows Drs. Nandini
Verma and Anna-Katharina Müller of the Weizmann Institute of Science's
Molecular Cell Biology Department and colleagues identified a subset of
triple negative breast cancer patients whose tissue samples expressed
higher levels of two particular molecules: EGFR and PYK2. EGFR - a
cell-surface receptor - has been implicated in a number of cancers when
it is overexpressed due to mutations. PYK2 - a robust molecule
previously discovered by Lev - plays a key role in breast cancer
The scientists found that, in animal models, inhibiting either of
these molecules alone led to a slight tumor reduction, but inhibiting
them both together resulted in a more potent therapeutic effect, leading
to a significant decrease in tumor size.
Upon further investigation, Lev and her team were able to identify
the exact molecular pathways and protein interactions in which EGFR and
PYK2 involvement leads to tumor growth and survival, and the results
appear to explain the potent effect when they are inhibited together.
Most strikingly, the team discovered that inhibition of PYK2 not only
synergizes with the EGFR inhibitors but could also bypass the problem of
resistance to EGFR antagonists.
The reason why inhibiting EGFR alone does not seem to afford much
clinical benefit, the scientists believe, is that cells tend to
compensate for the lack of EGFR by increasing levels of an alternative
receptor molecule called HER3, which is associated with drug resistance
to EGFR therapy.
The scientists found that inhibiting the second
molecule, PYK2, in addition to curtailing cancer growth and metastasis,
also sets in motion an additional chain of events that ultimately marks
HER3 for degradation. Helping to rid the cells of HER3 allows EGFR
therapy to work more effectively.
We believe that this combination therapy - targeting both EGFR and
PYK2 - provides a promising, more effective approach for a subset of
triple negative breast cancer patients than other combinations that are
currently being tested, owing to its ability to impede tumor growth and
survival and prevent drug resistance," says Lev.
About one-fifth of all breast cancers are triple negative, which
means that more than 300,000 women worldwide are diagnosed every year
with this form of malignancy.