Dual-Action Inhibition Strategy for KRAS and LKB1 Mutant NSCLC

NU 2023-113

INVENTORS

• Lillian Eichner (Feinberg School of Medicine, Department of Biochemistry and Molecular Genetics)*
• Reuben Shaw (Salk Institute)

SHORT DESCRIPTION
A dual drug combination to target KRAS and LKB1 mutant non–small cell lung cancer that results in superior efficacy by enhancing T cell recruitment and reducing tumor burden.

BACKGROUND
Lung cancer remains the leading cause of cancer deaths in the United States. Approximately 85% of lung cancers are non–small cell lung cancer, which is associated with significant treatment challenges. Current therapies often fail for patients with KRAS and LKB1 mutations due to poor responsiveness to chemotherapy and immunotherapy. This unmet need drives the search for improved treatment strategies.

ABSTRACT
Northwestern researchers have developed a combination treatment that pairs a KRAS inhibitor with an HDAC inhibitor to treat NSCLC harboring KRAS and LKB1 mutations. Their studies determined that HDAC3 functions as a transcriptional repressor of chemokines critical for T cell recruitment. Genetic and pharmacological approaches to inhibit HDAC3 activated these chemokine genes in both human and mouse cancer cells. In mouse models, the combination treatment enhanced T cell recruitment and reduced tumor burden by 79% without any observed toxicity. These findings establish the potential of this dual drug approach to overcome therapeutic resistance in KRAS mutant lung cancers.

DEVELOPMENT STAGE
TRL-4 - Prototype Validated in Lab: Key functions have been demonstrated in laboratory-scale models showing significant tumor reduction and enhanced T cell recruitment.

APPLICATIONS

• Targeted therapeutic for NSCLC with KRAS and LKB1 mutations
• Combination treatment to overcome resistance in drug-refractory lung cancers

ADVANTAGES

• Overcomes KRAS inhibitor resistance by using a dual drug approach
• Employs clinical well-tolerated drugs for improved patient outcomes
• Reduces tumor burden by 79% in preclinical models
• Exhibits minimal toxicity in animal studies

PUBLICATIONS

• Lillian Eichner et al, HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non–small cell lung cancer, Sci Adv, Mar 17, 2023.
• Lillian Eichner et al, Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors, Proc Natl Acad Sci U S A, Oct 10, 2024.

IP STATUS
US patent pending (18/734,662).

CATEGORY/INDUSTRY PIPELINE
Therapeutics

KEYWORDS
NSCLC, lung cancer, oncology, targeted therapy, combination treatment, immunotherapy, KRAS mutation, LKB1 mutation, KRAS inhibitor, HDAC inhibitor