SUMMARY OF INVENTION
The KRAS oncogene is associated with a poor prognosis in metastatic cancers and also with a high risk of cancer recurrence. Amplified in ~15-25% of lung adenocarcinomas, KRAS has proved to be an elusive target to drug, with single-agent therapeutics targeting pathways downstream of KRAS lacking efficacy.
Through a small hairpin RNA (shRNA) screen, MSK investigators identified FGFR1 as sensitizing KRAS-mutant lung cancer cells to a MEK inhibitor. Furthermore, MSK investigators found that combining a MEK inhibitor with an FGFR inhibitor showed activity in treating human KRAS-mutant pancreatic cancer cells and KRAS-mutant lung adenocarcinoma cells, with distinct inhibition of cell proliferation. In vivo, suppressing FGFR1 in combination with MEK led to regression of KRAS-mutant lung tumors in both KRAS-mutant lung cancer xenografts as well as a genetically engineered mouse model. Investigators determined that inhibiting MEK induces FGFR1 signaling in KRAS-mutant lung tumors, thereby providing mechanistic support for combination MEK/FGFR1 therapy.
Combination therapy of a MEK inhibitor combined with a FGFR1 inhibitor could address the large unmet need in clinical oncology of treating patients with KRAS-mutant lung adenocarcinoma
Investigators have demonstrated mechanistic support for MEK/FGFR1 inhibition, with FGFR1 mediating adaptive drug resistance caused by MEK inhibition
Lung cancer is the most common cancer worldwide. Approximately 40% of lung cancers are adenocarcinomas, and approximately 15–25% of patients with lung adenocarcinoma have tumor-associated KRAS mutations. These mutations are found in both tumors from current/former smokers, as well as never-smokers. In 2016, there will be an estimated ~23K new cases of KRAS-mutant lung adenocarcinoma in the U.S., and there are over ~41K patients currently living with KRAS-mutant lung adenocarcinoma in the U.S. There is a strong unmet need for an effective therapy, since prognosis is poor, with overall survival at about 14 months for patients with KRAS-mutated lung adenocarcinoma.
Manchado, E. et al., A combinatorial strategy for treating KRAS-mutant lung cancer. Nature, 2016 Jun 30;534(7609):647-51. (PubMed ID: 27338794)
AREAS OF APPLICATION
Initial application in KRAS-mutant lung cancer
STAGE OF DEVELOPMENT
In vivo data
PCT application (PCT/US2016/017750) filed on February 12, 2016
Scott Lowe, PhD, Chair and Laboratory Head, Cancer Biology and Genetics Program, Sloan Kettering Institute, MSK