Novel Combination Therapy for Treating KRAS-Mutant Lung Cancers

SK2015-001

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.

ADVANTAGES

  • 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

     

MARKET OPPORTUNITY

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.

PUBLICATION

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

PATENT INFORMATION

PCT application (PCT/US2016/017750) filed on February 12, 2016

LEAD INVESTIGATOR

Scott Lowe, PhD, Chair and Laboratory Head, Cancer Biology and Genetics Program, Sloan Kettering Institute, MSK

CONTACT INFORMATION

Eileen Flowers, PhD, Licensing Manager
Tel: 646-888-1067

E-mail: flowerse@mskcc.org

Stage of Development

Animal studies

Indications

Types