Lilly Targets Faulty c-MET Receptor in Cancer Research Studies Presented Today at AACR Meeting
CHICAGO, April 2, 2012 /PRNewswire/ — Eli Lilly and Company (NYSE: LLY) today
announced results of three preclinical studies focused on c-MET, a receptor
tyrosine kinase that, when it functions normally, plays a key role in
transmitting signals within a cell. Abnormalities in c-MET function and
signaling have been found in many types of cancer including lung, breast,
prostate, gastric, esophageal and renal cancers.
Two of the abstracts (#2734 and #2738) assess the anti-cancer activity of
Lilly’s LY2875358, a humanized IgG4 monoclonal antibody directed against c-MET
currently in Phase II clinical development, while the third (#1738) looks at a
Lilly assay for detecting c-MET expression levels in circulating tumor cells
(CTCs) that are shed into the bloodstream. The data were presented today during
the American Association for Cancer Research (AACR) 103rd Annual Meeting in
“Our c-MET program includes two different potential medicines in Phase I and II
development–a monoclonal antibody and a small molecule inhibitor–that both
target a receptor believed to play a critical role in the development of some
cancers,” said Richard Gaynor, M.D., vice president of product development and
medical affairs at Lilly Oncology. “Our job now is to discover if these
potential medicines will inhibit the growth of certain cancers, and identify
which patients would specifically benefit for treatments such as these.”
Identifying and Exploring c-MET
Normally, c-MET signaling is activated when its only known ligand–the hepatic
growth factor (HGF)–binds to the c-MET receptor. c-MET signaling is necessary
for normal embryonic development, particularly of the liver, as well as for
liver regeneration and wound healing. Dysregulated c-MET signaling can cause
cell proliferation, increased cell survival, angiogenesis, invasion, metastasis
and drug resistance.
In cancer cells, c-MET signaling can become active in two ways: either by
binding of its ligand HGF (i.e., ligand-dependent mechanisms) or by
ligand-independent mechanisms, such as gene amplification or activating
mutations. The c-MET antibody LY2875358 is capable of blocking both
ligand-dependent and ligand-independent c-MET activations. LY2875358 binds to
c-MET, which prevents the c-MET ligand HGF from binding, but also induces
internalization and degradation of c-MET, thereby blocking ligand-independent
c-MET signaling caused by overexpression, amplification or mutation of c-MET.
Because LY2875358 affects both ligand-dependent and ligand-independent
mechanisms, binding of this antibody to c-MET-expressing tumor cells has the
potential to inhibit c-MET-driven tumor proliferation.
Abstract #2734: c-MET antibody LY2875358 (LA480) has enhanced efficacy with
gastric cancer standard-of-care in vitro and in vivo
One of the ligand-independent causes of aberrant c-MET signaling–amplification
of the c-MET gene–has been observed in 10 percent to 20 percent of gastric
tumors. Gene overexpression due to these extra copies of the c-MET gene is
associated with poor prognosis in gastric cancer patients.
In vitro, this study found that LY2875358 successfully reduced cell
proliferation in gastric cancer cell lines in which c-MET activation was caused
by c-MET overexpression. LY2875358 appeared to deplete the c-MET molecules from
the surface of the cancer cells. In vivo, in an animal model to which human
gastric tumors were grafted, LY2875358 alone showed marked antitumor activity.
The combination of LY2875358 therapy and standard chemotherapy was more
effective than either treatment alone both in vitro and in vivo, suggesting that
combining LY2875358 with standard chemotherapy may be a promising approach for
treating gastric cancer.
Abstract #2738: c-MET antibody LY2875358 (LA480) shows differential antitumor
effects in non-small cell lung cancer
Aberrant c-Met expression occurs in 41 percent to 72 percent of cases of
non-small cell lung cancer (NSCLC); amplification of the c-MET gene is present
in 5 percent to 10 percent of cases.
This study found that LY2875358, either alone or combined with standard
chemotherapy, inhibits cell proliferation and migration, as well as signal
transduction in NSCLC cells in which the c-MET gene was amplified, mutated or
In vitro, LY2875358 induces c-MET degradation in both wild type and mutant c-MET
cells. In vivo, in an animal model bearing human NSCLC tumors produced by c-MET
amplification, LY2875358 alone showed marked antitumor activity. The combination
of LY2875358 with standard chemotherapy produced better efficacy than either
treatment alone, both in vitro and in vivo.
Abstract #1738: Assay development for detecting c-MET expression in circulating
tumor cells (CTC), a potential patient tailoring marker for evaluation of c-MET
Patients with cancers in which the c-MET gene is amplified or overexpressed
typically have a poor prognosis. Lilly scientists hypothesized that such
patients would be especially likely to benefit from experimental therapies such
as LY2875358, which target c-MET. What was needed was a noninvasive technique
for monitoring the effectiveness of c-MET inhibitors over the course of
One noninvasive alternative to the standard biopsy is to count the CTCs present
in a patient’s blood sample. These cells, which are shed by tumors, appear
representative of cells migrating from primary tumors to form distant
metastases. The greater the number of CTCs found in a blood sample, the worse
the patient’s prognosis.
Lilly scientists evaluated the development of an assay that counts the number of
CTCs in a blood sample and measures their c-MET expression to potentially
determine which patients may respond better to agents such as LY2875358 that
target c-MET. Scientists first collected cells from several cultured cell lines
that were derived from solid epithelial tumors and had different c-MET
expression levels. Initially, mouse blood was spiked with the cells from the
various cell lines. Those results were later successfully reproduced using human
whole blood from healthy subjects, to which tumor cells were added.
After the mouse and human blood was spiked with tumor cells, the CTCs were
collected and counted. A Lilly proprietary c-MET antibody, optD11, was then used
to determine the c-MET expression levels of the collected cells.
The optD11 antibody was used in this assay for several reasons. It could detect
different c-MET expression levels among several cell lines in which c-MET was
expressed at high levels, and it could successfully identify a different cell
line as not having aberrant c-MET gene expression. Equally important, the optD11
antibody could function in the presence of the Lilly therapeutic antibody
LY2875358. This means that the Lilly assay can monitor c-MET gene expression
levels in patients being treated with LY2875358.
This Lilly assay for measuring c-MET expression levels in CTCs–and a different
Lilly assay that measures c-MET gene amplification in CTCs–are now being used
in early phase clinical studies evaluating additional c-MET inhibitors being
developed in Lilly laboratories.
For more information on Lilly’s c-MET antibody, please visit
About Lilly Oncology
For more than four decades, Lilly Oncology, a division of Eli Lilly and Company,
has been dedicated to delivering innovative solutions that improve the care of
people living with cancer. Because no two cancer patients are alike, Lilly
Oncology is committed to developing novel treatment approaches. To learn more
about Lilly’s commitment to cancer, please visit www.LillyOncology.com.
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing
portfolio of pharmaceutical products by applying the latest research from its
own worldwide laboratories and from collaborations with eminent scientific
organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -
through medicines and information – for some of the world’s most urgent medical
This press release contains forward-looking statements about the potential of
LY2875358 and LY2801653 as treatments for various cancers and reflects Lilly’s
current beliefs. However, as with any pharmaceutical product, there are
substantial risks and uncertainties in the process of development and
commercialization. There is no guarantee that these products will be
commercially successful. For further discussion of these and other risks and
uncertainties, see Lilly’s filings with the United States Securities and
Exchange Commission. Lilly undertakes no duty to update forward-looking
SOURCE Eli Lilly and Company