A team of cancer researchers from several Boston academic medical centers has discovered a potential treatment for tumors driven by mutations in the K-Ras gene, which have resisted previous targeted therapy approaches.
Combining targeted therapy drugs may treat previously resistant tumors
Blocking two cell signalling pathways leads to dramatic shrinkage of K-Ras-mutated tumors in animal model
A team of
cancer researchers from several
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
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 K-Ras-stimulated tumors. That treatment was ineffective, but since K-Ras also activates the MEK/ERK signalling 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.
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
Wong, MD, PhD, of DFCI, 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 Dana-Farber.” Wong is an assistant professor of Medicine at
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 of Dana Farber Cancer Institute. Additional co-authors are Youngchul Song, and Ramneet Kaur, MGH Cancer Center; Alexander Guimaraes, Rabi Upadhyay, Ralph Weissleder and Umar Mahmood, MGH Center for Molecular Imaging Research; Xiaohong Tan, Kate McNamara and Samanthi Perera, DFCI; Timothy Li, BIDMC; Katherine Crosby, Angela Lightbown and Jessica Simendinger, Cell Signaling Technology; Michel Maira and Carlos Garcia-Echeverria, Novartis Institutes for Biomedical Research; Lucian Chirieac and Robert Padera, 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 Excellence grants.
Cancer Institute is a principal teaching affiliate of the
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