Nano‐Targeted Kinase Inhibitor Treatment of KRAS Mutant Lung Cancer

Abstract

Lung cancer is the leading cause of mortality in the US, affecting 160,000 patients annually with a five year survival of 17%. The majority of lung cancers harbor KRAS mutations that over‐activate the RAS kinase in the RAS‐MAPK signaling pathway, RAS‐RAF‐MEK‐ERK. This leads to increased pathway activity and increased cell division and tumor growth. Kinase inhibitors (KIs), which target key effectors of cancer signaling pathways, constitute a major strategy to treat KRAS‐driven lung cancer. Although RAS itself is difficult to drug with KIs due to the lack of binding pockets, KIs inhibiting downstream MEK kinases of the RAS‐MAPK pathway have shown to be most effective in vitro. However, MEK inhibitors suppress signaling in non‐cancer cells, so their dosing is limited by toxicity and results in a narrow therapeutic index. Additionally, the anti‐tumor effects of MEK inhibitors in KRAS‐driven lung cancer are further diminished by the activation of compensatory pathways, resulting in drug resistance and tumor resurgence. Although the co‐administration of a second KI can mitigate this resistance, many such combinations of KIs are highly toxic.We recently developed a new nanomedicine platform to package kinase inhibitors with high drug loading. These indocyanine nanoparticles (INPs) alter the systemic biodistribution of the KI to improve the drug's therapeutic index via tumor targeting. The INPs target caveolin receptors overexpressed on cancer endothelium to increase the local concentration of kinase inhibitor at the tumor site and reduce the systemic exposure of non‐cancerous tissues. Thus, the selective targeting decreases the toxicity of systemic KI exposure to concomitantly improve the therapeutic index.Support or Funding InformationThis work was supported in part by the NIH New Innovator Award (DP2‐HD075698), the Cancer Center Support Grant (P30 CA008748), the Pershing Square Sohn Cancer Research Alliance, the Honorable Tina Brozman Foundation for Ovarian Cancer Research, the Expect Miracles Foundation ‐ Financial Services Against Cancer, the Anna Fuller Fund, the Louis V. Gerstner Jr. Young Investigator's Fund, the Frank A. Howard Scholars Program, Cycle for Survival, the Alan and Sandra Gerry Metastasis Research Initiative, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, the Imaging & Radiation Sciences Program, and the Center for Molecular Imaging and Nanotechnology of Memorial Sloan Kettering Cancer.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.