Blocking two cell signaling pathways leads to dramatic shrinkage of K-Ras-mutated tumors in animal model
A team of cancer researchers from several Boston academic medical
centers has discovered a potential treatment for a group of tumors that
have resisted previous targeted therapy approaches.
In their Nature Medicine report, which is receiving early
online release, investigators from Dana-Farber Cancer Institute,
Massachusetts General Hospital (MGH) Cancer Center, and Beth Israel
Deaconess Medical Center (BIDMC) Cancer Center report that combining
two different kinase inhibitors — drugs that interfere with specific
cell-growth pathways — led to significant tumor shrinkage in mice with
lung cancer driven by mutations in the K-Ras gene.
In addition to their association with nearly 30 percent of cases of
non-small-cell lung cancer — the leading cause of cancer deaths in the
U.S. — K-Ras mutations are involved in many cases of colon cancer and
most pancreatic cancers, which are extremely resistant to treatment.
"Finding a way to effectively treat K-Ras-mutated cancers would be a
huge advance in solid tumor oncology, since these mutations are common
in several incurable cancers," says Jeffrey Engelman, MD, PhD, of the
MGH Cancer Center, one of the report's co-lead authors.
"Cancers with K-Ras mutations have been resistant to all targeted
therapies to date, and it is exciting to learn that a combination of
PI3K and MEK inhibitors, two families of drugs currently in clinical
development, may be highly effective in these cancers."
The current study began with a focus on the PI3K signaling pathway,
which is key to cell survival and known to control cellular motility
and adhesion. PI3K mutations have caused tumor development in
laboratory studies, but their role had not yet been studied in an
animal model. The research team developed a transgenic mouse in which
administration of the drug doxycycline induces the expression of
cancer-associated PI3K mutations, leading to development of lung tumors.
Treatment of those animals with an investigational PI3K inhibitor
did lead to rapid tumor regression. Since previous studies suggested
that PI3K inhibition might also block K-Ras-induced tumor development,
the investigators also tested the PI3K inhibitor in mice with
That treatment was ineffective, but since K-Ras also activates the
MEK/ERK signaling pathway, the researchers treated the animals with an
investigational MEK inhibitor and with a combination of both drugs.
Treatment with the MEK inhibitor alone caused only a modest reduction
in tumor size, but combined treatment with both agents caused the
K-Ras-stimulated lung tumors to virtually disappear.
"For several years we have known that K-Ras activates two major
pathways — the PI3K pathway and the MEK/MAPK pathway — and that these
pathways have many redundant functions in tumor growth and survival,"
says Lewis Cantley, PhD, of the BIDMC Cancer Center, one of the study's
"Inhibitors of both of these pathways are now in clinical trials,
and in this paper we show that, while either agent alone has a minor
effect on K-Ras-driven tumors in mice, combining inhibitors of both
pathways eradicates these tumors with minimal toxicity."
Kwok-Kin Wong, MD, PhD, of Dana-Farber, also a co-corresponding
author, adds, "The results of our study are truly remarkable and
provide a strong and compelling scientific rationale to test this
combination therapy in human phase 1 and 2 trials. This work would not
have been possible without the highly productive collaboration between
our laboratories at Mass. General, Beth Israel Deaconess and
Wong is an assistant professor of medicine at Harvard Medical
School, where Engelman is also an assistant professor in medicine and
Cantley is the Castle Professor of Medicine.
The researchers are hoping to advance towards clinical trials by
testing combination therapy against other models of K-Ras-mutated
cancer, including those that involve additional mutations in other
tumor-associated genes, and to investigate whether K-Ras-associated
tumors will become resistant to combination therapy, a problem that has
plagued other targeted cancer therapies.
The co-lead author of the Nature Medicine report is Liang
Chen, PhD, of Dana-Farber. Additional co-authors are Xiaohong Tan, MD,
PhD, Kate McNamara and Samanthi Perera, PhD, Dana-Farber; Youngchul
Song, and Ramneet Kaur, MGH Cancer Center; Alexander Guimaraes, MD,
Rabi Upadhyay, Ralph Weissleder, MD, PhD, and Umar Mahmood, MD, PhD,
MGH Center for Molecular Imaging Research; Timothy Li, BIDMC; Katherine
Crosby, Angela Lightbown and Jessica Simendinger, Cell Signaling
Technology; Michel Maira and Carlos Garcia-Echeverria, PhD, Novartis
Institutes for Biomedical Research; Lucian Chirieac, MD, and Robert
Padera, MD, PhD, Brigham and Women's Hospital.
The study was supported by grants from the National Institutes of
Health, the American Association for Cancer Research, the International
Association for the Study of Lung Cancer, the Joan Scarangello
Foundation to Conquer Lung Cancer, the Cecily and Robert Harris
Foundation, the Flight Attendant Medical Research Institute and several
Dana-Farber/Harvard Cancer Center Specialized Program of Research
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United
States. It is a founding member of the Dana-Farber/Harvard Cancer
Center (DF/HCC), designated a comprehensive cancer center by the
National Cancer Institute.
Massachusetts General Hospital (www.massgeneral.org),
the original and largest teaching hospital of Harvard Medical School,
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million.
Beth Israel Deaconess Medical Center (www.bidmc.harvard.edu)
is a patient care, teaching and research affiliate of Harvard Medical
School and consistently ranks among the top four in National Institutes
of Health funding among independent hospitals nationwide.