Exploring the therapeutic potential of novel KRAS inhibitors in lung cancer

2015

Piro Lito, MD, PhD

Memorial Sloan Kettering Cancer Center

New York

Dr. Lito is working with a new drug that works efficiently to stop the growth of lung cancer cells with a mutation in the KRAS gene. Funding from LUNGevity will provide resources to test the drug in mice that have KRAS-positive lung cancer. Dr. Lito’s ultimate aim is to develop a clinical trial for the drug for use in patients who test positive for a KRAS mutation.

Research Summary

KRAS mutations are found in approximately one-third of lung cancers, a disease that kills approximately 160,000 people annually in the U.S. The presence of KRAS mutations indicates a worse prognosis and may also suggest a worse outcome with standard therapy. Thus, the treatment of patients with this molecular subtype of lung cancer remains one the biggest challenges faced by medical oncologists.

This work will elucidate how KRAS G12C, the most frequent KRAS mutation in lung cancer, drives intracellular signaling and lung cancer. To do so, Dr. Lito and his group will use a novel inhibitor that specifically targets the mutated form of this protein. Ultimately this work will establish the first KRAS-directed targeted therapeutic approach to treat patients with lung cancer.

Technical Abstract

KRAS mutations activate signaling from downstream effector proteins and are though to be required for tumor formation. Exactly how effector signaling is activated, however, is not fully understood. In addition, whether tumors harboring KRAS mutations depend on this oncogene for growth is unclear.

Dr. Lito and his group will dissect the phenotype of KRAS-mutant lung cancer by using a novel allosteric inhibitor that selectively targets KRAS G12C. They will first utilize biochemical assays in order to determine the mechanism of action of this inhibitor. An emphasis will be placed on evaluating how feedback pathways modulate this process, since this is likely to identify factors that may be used as biomarkers of response to treatment.

They will then determine which effector pathways drive the phenotype of KRAS G12C mutant lung cancer, and whether these exhibit adaptation (or reactivation) over time. If so, they will next explore combination-based interventions in order to establish the most effective antiproliferative strategy.

Finally, they will utilize novel patient-derived xenograft and cell line models, established from patients with lung cancer treated at MSKCC, in order to determine if KRAS G12C mutant lung cancers depend on this oncoprotein for growth. These models will also be used to test the most effective combination strategies determined above, as well as to test the potential benefit of intermittent administration schemes designed to best target tumor adaptation to this novel class of inhibitors.

The grand objective of this project is to establish a mutant KRAS-directed therapy for patients with lung cancer.

Key words

Non-small cell lung cancer (NSCLC)

Stage - all

Targeted therapy

Exploring the therapeutic potential of novel KRAS inhibitors in lung cancer

LUNGevity Foundation

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