Two papers in The JCI suggest that suppressing mTOR with rapamycin as well as supressing the MAPK pathway, which rapamycin triggers, with another molecule is more effective in mouse models.
Two independent groups of investigators have found that simultaneous inhibition of the mTOR and MAPK pathways enhanced antitumor effects in mouse models of prostate and breast cancer.
Several rapamycin analogs known as mTOR (mammalian target of rapamycin) inhibitors have been tested in clinical trials. Investigations have been less successful than originally expected.
Now research published in August 21 advance online issue of The Journal of Clinical Investigation suggests that while rapamycin analogs halt tumor growth by inhibiting the mTOR protein complex 1 (mTORC1), they simultaneously also activate the MAPK (mitogen-activated protein kinase) pathway, encouraging cancer cell survival.
“We analyzed tissue from human biopsies as well as cancer cell lines and genetically engineered mouse models of cancer,” explains the study’s first author, Arkaitz Carracedo, Ph.D., a postdoctoral fellow at Beth Israel Deaconess Medical Center (BIDMC) identifies. “These experiments all pointed to the MAPK pathway.”
Dr. Carracedo and his group then tested a group of MAPK inhibitor in combination with mTOR inhibitors. They found that the together the agents countered any pro-survival activity.
Researchers from Memorial Sloan-Kettering Cancer Center, Whitehead Institute for Biomedical Research, the University of Cincinnati, Harvard Medical School, and the University Hospital in Barcelona contributed to this study.
In the second paper also published in the JCI, scientists found that simultaneous inhibition of the mTOR and MAPK signaling pathways suppressed the in vitro growth of prostate cancer cell lines. It also stopped the in vivo growth of prostate tumors in a mouse model of the disease. This was particularly true in a model of highly aggressive and frequently lethal forms of the disease, which do not respond to hormone deprivation therapy.
This study was done by investigators at Columbia University College of Physicians and Surgeons, University Clinic of Basel, Memorial Sloan-Kettering Cancer Center, and the University of Medicine & Dentistry of New Jersey, Piscataway.
