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Published on: July 21, 2018
MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer
Shunsuke Kitajima1, Tetsuo Tani2, Benjamin F Springer3
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, Japan.
Abstract:
KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.
Insights
KRAS-LKB1 mutant lung cancers evade immunotherapy by silencing STING. Transient MPS1 inhibition, combined with epigenetic therapy, reactivates this pathway, restoring T cell infiltration and enhancing anti-PD-1 efficacy for durable responses.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- KRAS-LKB1 (KL) mutant lung cancers exhibit intrinsic mitochondrial dysfunction, leading to STING silencing.
- This STING silencing results in T cell exclusion and resistance to PD-(L)1 blockade.
- KL cells also minimize 2'3'-cGAMP accumulation to evade STING and STAT1 activation.
Purpose of the Study:
- To identify therapeutic strategies to overcome immune evasion in KL mutant lung cancers.
- To explore the potential of targeting STING-STAT1 pathway reactivation.
Main Methods:
- Unbiased drug screening to identify vulnerabilities in KL cells.
- Utilizing transient MPS1 inhibition (MPS1i) to induce micronuclei generation.
- Investigating the synergistic effect of MPS1i with epigenetic de-repression of STING.
Main Results:
- Transient MPS1 inhibition potently re-engages the STING pathway in KL cells via micronuclei generation.
- Epigenetic de-repression of STING markedly amplifies the effect of MPS1i.
- A combination of decitabine and pulse MPS1i restored T cell infiltration in vivo.
- This combination therapy enhanced anti-PD-1 efficacy, leading to durable responses with minimal toxicity.
Conclusions:
- Targeting STING pathway reactivation presents a promising therapeutic approach for KL mutant lung cancers.
- The combination of epigenetic therapy and pulse MPS1 inhibition offers a viable strategy to overcome immune resistance.
- This approach demonstrates potential for durable responses in lung cancer patients resistant to current immunotherapies.
