Even when their tumors are shrinking in response to therapy, some
non-small cell lung cancer (NSCLC) patients have a scattering of cancer
cells that are undeterred by the drug, causing the tumor to resume its
growth, Dana-Farber Cancer Institute and Massachusetts General Hospital
(MGH) Cancer Center scientists report in the January issue of Cancer Cell.
The findings suggest that identifying such patients and treating them
with a combination of drugs from the very start of therapy can produce
The study involves NSCLC tumors that are driven by a mutation in the gene EGFR.
Such tumors, which account for about 12 percent of all NSCLC cases in
the United States, often recede when treated with a tyrosine kinase
inhibitor such as Tarceva® or Iressa®, which targets the faulty EGFR
An EGFR mutant non-small cell lung cancer harboring a small
population of drug resistant cells (red) prior to drug exposure. These
cells contain an amplification of MET. (Image: Eric D. Smith)
A few years ago, this same group of investigators showed that NSCLCs
being held in check by Tarceva can switch on an alternate growth circuit
if they have too many copies of a gene called MET. Such tumors are considered Tarceva- and Iressa-resistant.
In the new paper, investigators led by Pasi Jänne, MD, PhD, of Dana-Farber, and Jeffrey Engelman, MD, PhD, of MGH, found that some patients with EGFR-mutant lung cancers harbor a small number of tumor cells with an overabundance, or "amplification," of MET even before treatment with a tyrosine kinase inhibitor, and that those few cells are enough to spark drug resistance.
One of the triggers for resistance, the researchers found, is HGF, a ligand or "hook" that activates the MET protein.
When activated, HGF works through two entirely different channels to
produce drug resistance, the authors report. First, it can generate
cell-growth signals through a protein called GAB1. Second, it expands
the number of MET-amplified cancer cells, ensuring they will become the dominant type in the lung tumors.
"Not only can HGF spur cell growth on its own, it can speed up the process by which MET-amplified
cells emerge and take over the composition of the tumor," says Jänne,
who was co-senior author of the paper with Engelman.
In about 20 percent of NSCLC patients who are resistant to Tarceva the mechanism is amplification of MET, and in another 20 percent it may involve HGF.
The findings suggest that patients whose NSCLC tumors harbor even a few MET-amplified
cells prior to treatment would benefit from drugs that specifically
target those cells, in combination with a tyrosine kinase inhibitor.
Jänne notes that such drugs are already being studied in clinical
"Our findings provide a strong rationale for combination treatment
strategies as initial therapies for some patients," Jänne remarks. "This
is especially the case in patients with evidence of pre-existing MET amplifications."
Engelman adds, "A thorough analysis of a patient's cancer prior to
treatment can establish how it would ultimately develop resistance to
therapy, allowing us to tailor treatment with greater precision to
"For example, cancers found to harbor a small population of cells with pre-existing MET
amplification will likely benefit from adding MET inhibitors to initial
treatment. Those without such cells may not benefit, and these patients
can avoid the added toxicity of MET inhibitors and instead focus on
other strategies to prevent their cancers from becoming resistant."
Engelman is an assistant professor of medicine and Jänne an associate professor of medicine at Harvard Medical School.
The study was supported by grants from the National Institutes of
Health, American Association for Cancer Research, the V Foundation,
American Cancer Society, Hazel and Samuel Bellin Research Fund, and the
The study's co-lead authors were Alexa Turke of MGH, and Kreshnik
Zejnullahu, of Dana-Farber. Co-authors include Yi-Long Wu, of Guangdong
General Hospital, Guangzhou, China; Youngchul Song, Dora
Dias-Santagata, PhD, Eugene Lifshits, Lecia Sequist, MD, MPH, Sara
Akhavanfard, MD, Beow Yeap, and A. John Iafrate, MD, PhD, of MGH; Luca
Toschi, MD, Andrew Rogers, and Marzia Capelletti of Dana-Farber; Tony
Mok, MD, of the Chinese University of Hong Kong; Neal Lindeman, MD,
Carly Murphy, Yun Xiao, and Charles Lee, PhD, of Brigham and Women's
Hospital; and James Christensen, of Pfizer Global Research and
Development, La Jolla, Calif.