KANAZAWA, Japan, Sept. 16, 2020 /PRNewswire/ -- Researchers at
Kanazawa University report in Nature Communications the
mechanism making some lung-cancer patients resistant to the drug
osimertinib. In addition, they suggest a combined drug treatment
resolving osimertinib resistance in the case of cancer cells
expressing low amounts of AXL, a protein belonging to the class of
receptor tyrosine kinases.
The effectiveness of cancer treatment is often hampered by
cancer cells being heterogeneous. This is the case for
EGFR-mutated lung cancer: drugs based on biomolecules of a type
known as tyrosine kinase inhibitor (TKI) have been used to treat
the disease, but with various levels of efficacy. (EGFR stands for
"epidermal growth factor receptor", a protein playing an important
role in signaling processes from the extracellular environment to a
cell.) Sometimes, tumor cells are simply resistant to the drug.
Now, Seiji Yano from Kanazawa
University and colleagues have investigated the efficacy of the TKI
osimertinib for treating EGFR-mutated lung cancer, and how it
relates to the expression in tumor cells of a particular protein
called AXL. They found that both AXL-high and -low expressing
tumor cells showed tolerance (acquired resistance) to osimertinib,
but that the mechanisms involved are different for the two
situations. Moreover, the researchers suggest a way to
enhance the success of osimertinib treatment for the case of
AXL-low expressing tumors.
First, the scientists compared the susceptibility to osimertinib
in both AXL-high and -low expressing tumor cells in in vitro
experiments. They observed that osimertinib inhibited the
viability of the cancer cells in both cases, but that the
sensitivity to the drug was higher for AXL-low expressing
EGFR-mutated lung cancer cells. They also noticed that a small
number of tumor cells survived the procedure — an indication of
osimertinib tolerance. These findings were consistent with
results from the clinical study of the drug performed earlier on 29
patients with EGFR-mutated non-small cell lung cancer.
Through experiments aiming to understand the mechanism behind
osimertinib tolerance, Yano and colleagues discovered that
phosphorylation of IGF-1R was increased in AXL-low-expressing tumor
cell lines, but not in AXL-high expressing tumors. (IGF-1R stands
for 'insulin-like growth factor 1 receptor'; it is a protein
located on the surface of human cells. Phosphorylation is the
chemical process of adding a phosphoryl group.) The
researchers then found that phosphorylated IGF-1R supported the
survival of AXL-low expressing tumors after exposure to
osimertinib.
The scientists then tested whether the observed osimertinib
resistance could be resolved by administering linsitinib, a
substance known to inhibit the phosphorylation of IGF-1R.
Encouraged by the positive outcome of the experiment, Yano and
colleagues went further and evaluated the combination of
osimertinib and linsitinib. Their conclusion was that the
transient combination of linsitinib with continuous osimertinib
treatment could cure or at least dramatically delay tumor
recurrence in AXL-low-expressing EGFR-mutated lung cancer.
More investigating needs to be done, though. Quoting the
researchers: "… the safety and efficacy of the transient
combination of IGF-1R inhibitor and osimertinib should be evaluated
in the clinical trials."
Background
Tyrosine kinase inhibitors
A tyrosine kinase inhibitor is a drug inhibiting (that is,
preventing or reducing the activity of) a specific tyrosine kinase.
A tyrosine kinase is a protein (enzyme) involved in the activation
of other proteins by signaling cascades. The activation happens by
the addition of a phosphate group to the protein (phosphorylation);
it is this step that a tyrosine kinase inhibitor inhibits.
Tyrosine kinase inhibitors are used as anticancer drugs. One
such drug is osimertinib, used to treat EGFR-mutated lung
cancer.
AXL
AXL is a receptor tyrosine kinase — a tyrosine kinase consisting
of an extracellular part, a transmembrane part ('sitting' within a
cell membrane) and an intracellular part. AXL regulates
various important cellular processes, including proliferation,
survival and motility.
In recent years, it has become clear that AXL is a key
facilitator of drug tolerance by cancer cells. Seiji Yano from Kanazawa University and
colleagues have found that this is also the case for EGFR-mutated
lung cancer. While a high expression of AXL correlates with
resistance to osimertinib, such tolerance also occurs in
AXL-low-expressing cancer cells. Yano and colleagues have now
found that for the latter case, phosphorylation of IGF-1R
(insulin-like growth factor 1 receptor) is responsible for the
resistance to osimertinib.
Reference
Rong Wang, Tadaaki Yamada,
Kenji Kita, Hirokazu Taniguchi, Sachiko Arai, Koji
Fukuda, Minoru Terashima,
Akihiko Ishimura, Akihiro Nishiyama, Azusa
Tanimoto, Shinji Takeuchi,
Koshiro Ohtsubo, Kaname Yamashita,
Tomoyoshi Yamano, Akihiro Yoshimura, Koichi Takayama, Kyoichi
Kaira, Yoshihiko Taniguchi,
Shinji Atagi, Hisanori Uehara, Rikinari Hanayama, Isao Matsumoto, Xujun
Han, Kunio Matsumoto,
Wei Wang, Takeshi Suzuki, and Seiji Yano. Transient IGF-1R inhibition combined
with osimertinib eradicates AXL-low expressing EGFR mutated lung
cancer, Nature Communications 11, XX (2020).
DOI: 10.1038/s41467-020-18442-4
URL: https://doi.org/10.1038/s41467-020-18442-4
Link to figure
https://nanolsi.kanazawa-u.ac.jp/wp-content/uploads/2020/09/Figure-768x567.png
Figure Caption
Mechanism of targeted drugs tolerance
in lung cancer cells
Further information
About WPI NanoLSI Kanazawa University
Hiroe Yoneda
Vice Director of Public Affairs
WPI Nano Life Science Institute (WPI-NanoLSI)
Kanazawa University
Kakuma-machi, Kanazawa 920-1192, Japan
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Nano Life Science Institute (NanoLSI), Kanazawa University is a
research center established in 2017 as part of the World Premier
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Education, Culture, Sports, Science and Technology. The objective
of this initiative is to form world-tier research centers. NanoLSI
combines the foremost knowledge of bio-scanning probe microscopy to
establish 'nano-endoscopic techniques' to directly image, analyze,
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life phenomena such as diseases.
About Kanazawa
University
http://www.kanazawa-u.ac.jp/e/
As the leading comprehensive university on the Sea of
Japan coast, Kanazawa University
has contributed greatly to higher education and academic research
in Japan since it was founded in
1949. The University has three colleges and 17 schools offering
courses in subjects that include medicine, computer engineering,
and humanities.
The University is located on the coast of the Sea of
Japan in Kanazawa – a city rich in
history and culture. The city of Kanazawa has a highly respected
intellectual profile since the time of the fiefdom (1598-1867).
Kanazawa University is divided into two main campuses: Kakuma and
Takaramachi for its approximately 10,200 students including 600
from overseas.