Researchers Discover How to Overcome Drug Resistance in Deadliest Cancers With Few Available Targeted Therapies
Study Also Finds Biomarkers That Could Predict a Patient’s Response
Mount Sinai researchers have discovered a new drug combination that could provide the first targeted therapy for some of the deadliest cancers, as well as molecular predictors of tumor response to the therapy, according to a study published in Cell Reports in January.
Certain of these deadly cancers, including triple-negative breast cancer as well as pancreatic, lung, and colorectal cancers, occur when normally occurring proteins, including those called KRAS or BRAF, in the cells mutate and cause tumors. These tumors are responsive to small-molecule drugs called RAF and MEK inhibitors; however, drug resistance limits the effectiveness of these therapies. The Mount Sinai researchers found that adding another small molecule, called an SHP2 inhibitor, can prevent drug resistance in many patients with these tumors. The newly discovered drug combination would strengthen the effect of the RAF and MEK inhibitors by slowing, and potentially stopping, the cancer’s ability to build up resistance to the drugs.
“Our findings provide a blueprint for the clinical development of this potentially powerful treatment strategy for a large portion of patients with triple-negative breast cancer or other tumors that that are driven by mutated proteins like KRAS and BRAF,” said the study’s lead author, Poulikos I. Poulikakos, PhD, Assistant Professor of Oncological Sciences at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.
The study also identified biomarkers that could predict a patient’s response to the combination therapy, providing a roadmap for the translation of this strategy to the clinic. Scientists made the discoveries by integrating biochemical studies with preclinical assessment of the drug combination using cancer tumor cell lines and tumors engrafted in mice.
The study was funded by the Dermatology Foundation, the Melanoma Research Foundation, the Melanoma Research Alliance, the Sidney Kimmel Foundation for Cancer Research, a Tisch Cancer Institute developmental award, a Breast Cancer Research Foundation grant, a 2017 Robin Chemers Neustein Postdoctoral Fellowship award and by the National Cancer Institute (R01CA204314 and T32CA078207).
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system encompassing (with the addition of South Nassau Communities Hospital) eight hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.