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Combination Decitabine and MPS1 Inhibitor Therapy for KRAS-LKB1 Mutant Lung Cancer

Therapeutic combinations of epigenetic inhibition followed by MSP1 inhibition for KL-mutant lung cancer patients

Therapeutics

Project Overview

It is estimated that 25-30% of NSCLC patients present mutations in the KRAS gene, approximately half of whom have deletions or inactivating mutations in the LKB1 gene.
KRAS-LKB1 (KL) mutant lung cancers are known to epigenetically silence stimulator of interferon genes (STING). There is a need to gain a deeper understanding of this pathway and develop novel therapeutic strategies for the treatment of KL-mutant lung cancers.
Dana-Farber researchers have discovered a new treatment to restore the STING pathway in KL-mutant cancer cells.
Dana-Farber is seeking a licensee for this technology.

Technology

Lung cancer is the second most common cancer worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 84% of lung cancers. It is estimated that 25-30% of NSCLC patients present mutations in the KRAS gene, approximately half of whom have deletions or inactivating mutations in the LKB1 gene.

KRAS-LKB1 (KL) mutant lung cancers are known to epigenetically silence stimulator of interferon genes (STING), which is activated by a second messenger produced by cyclic guanosine monophosphate (cGAS). Inhibition of the STING pathway suppresses anti-tumor interferon signaling, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-L1) blockade.

Dr. David Barbie’s lab has discovered that treatment with a DNA-damaging agent (e.g., an MPS1 inhibitor [MPS1i] such as BAY1217389) can restore STING in KL-mutant cancer cells via micronuclei generation following treatment with an epigenetic inhibitor, such as decitabine. For example, in one experiment using a pulse treatment strategy, KL tumors were treated for 7 days with decitabine, followed by 2 days of MPS1i, and an additional 2-day MPS1i treatment 2 weeks later. A majority of the mice (6/7) demonstrated a complete response that persisted after 80 days of treatment. KL tumors largely retain cGAS expression despite silencing of the STING pathway.

This treatment is effective because it induces cancer cells to sense micronuclei, which potently activate cGAS, thereby reversing STING silencing. In addition, the treatment demonstrates in vivo efficacy by restoring T cell infiltration and enhancing anti-PD-1 efficacy without resulting in significant toxicity.

Further Details:

Barbie DA, et al. MPS1 Inhibition Primes Immunogenicity of KRAS-LKB1 Mutant Lung Cancer, Cancer Cell 2022, (40)10, 1128-1144

Team Members: David Barbie, MD, Prafulla Gokhale, PhD, Cloud Paweletz, PhD, Tetsuo Tani, MD, PhD

Applications

Therapeutic combinations of epigenetic inhibition followed by MSP1 inhibition for KL-mutant lung cancer patients, with potential for targeting other tumor types.
Using high DNA methyltransferase (DNMT) levels and tumor cell STING negativity determined by immunohistochemistry as a biomarker for KL-mutant lung cancer.

Opportunities

Dana-Farber is seeking a Licensee for this technology.

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