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Targeting CRTC2 reverses STK11 mutant NSCLC tumor resistance to immunotherapy
Dimitri Robay1, Ole Ackermann1, Laurent Laborde1
1Novartis Biomedical Research, Oncology, Basel 4056, Switzerland.
Abstract:
Non-small cell lung cancer (NSCLC) patients with tumors harboring STK11 mutations are resistant to standard of care anti-PD-1/PD-L1 blockade. For this patient population there are no currently available tailored treatments, underlying the critical need to discover effective therapeutic strategies. In this study, we dissected the molecular mechanisms responsible for STK11-mediated resistance to immune checkpoint blockade (ICB) and identified CRTC2, a coactivator of the transcription factor cAMP response element-binding protein (CREB), as a key signaling node regulating Stk11-dependent cell-extrinsic functions. CRTC2 deletion remodeled the immune profiles of Stk11-KO tumors and resensitized them to anti-PD-1 treatment, comparably to Stk11-proficient tumors. Mechanistically, the abrogation of the binding between CRTC2 and CREB was sufficient to restore sensitivity to immunotherapy. These findings provide critical insights into the central role of CRTC2 in modulating response to ICB and identify the disruption of CRTC2-CREB interaction as a potential therapeutic approach for this patient population.
Insights
STK11 mutations in non-small cell lung cancer cause resistance to immunotherapy. Disabling the CRTC2-CREB interaction resensitizes tumors to anti-PD-1 treatment, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) with STK11 mutations shows resistance to anti-PD-1/PD-L1 immunotherapy.
- Lack of targeted treatments for this patient group necessitates novel therapeutic strategies.
Purpose of the Study:
- To investigate the molecular mechanisms behind STK11-mediated resistance to immune checkpoint blockade (ICB).
- To identify potential therapeutic targets for overcoming this resistance.
Main Methods:
- Utilized STK11-knockout (KO) tumor models.
- Assessed the role of CRTC2, a CREB coactivator, in regulating STK11-dependent functions.
- Investigated the impact of CRTC2 deletion and CRTC2-CREB interaction abrogation on tumor immune profiles and immunotherapy response.
Main Results:
- CRTC2 deletion remodeled immune profiles in STK11-KO tumors.
- CRTC2 deletion resensitized STK11-KO tumors to anti-PD-1 treatment.
- Disrupting the CRTC2-CREB interaction restored sensitivity to immunotherapy.
Conclusions:
- CRTC2 plays a pivotal role in modulating response to ICB in STK11-mutated NSCLC.
- Targeting the CRTC2-CREB interaction presents a promising therapeutic avenue for patients resistant to current immunotherapies.
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