Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown
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Abstract
Abstract Mutations in the STK11 (LKB1) gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non–small cell lung cancer (NSCLC) enrolled in three phase I/II trials. STK11 mutations were associated with resistance to the anti–PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of KRAS mutational status, highlighting STK11 as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood, and serum revealed a unique immune phenotype in patients with STK11 mutations, with increased expression of markers associated with neutrophils (i.e., CXCL2, IL6), Th17 contexture (i.e., IL17A), and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout models. These results suggest that STK11 mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. Significance: Patients with nonsquamous STK11-mutant (STK11mut) NSCLC are less likely than STK11 wild-type (STK11wt) patients to respond to anti–PD-L1 ± anti-CTLA4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in STK11mut NSCLC. This article is highlighted in the In This Issue feature, p. 2659
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STK11 knockout was sufficient to induce an immune-suppressive environment in MC38 tumors.
“Additionally, STK11 knockout led to an increase in intratumoral MDSCs (Supplementary Fig. S1C), indicating that STK11 knockout was sufficient to induce an immune-suppressive environment in MC38 tumors in a manner consistent with STK11 loss-of-function in human tumors (8, 21).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [21]
In the CT26 model, knockout of STK11 led to increased resistance to anti-PD-1.
“In the CT26 model, knockout of STK11 also led to increased resistance to anti–PD-1, as expected (21).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [21]
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- Authors
- Pore, N., Wu, S., Standifer, N., Jure-Kunkel, M., de los Reyes, M., Shrestha, Y., Halpin, R., Rothstein, R., Mulgrew, K., Blackmore, S., Martin, P., Meekin, J., Griffin, M., Bisha, I., Proia, T. A., Miragaia, R. J., Herbst, R., Gupta, A., Abdullah, S. E., Raja, R., Frigault, M. M., Barrett, J. C., Dennis, P. A., Ascierto, M. L., & Oberst, M. D.
- Affiliations
- AstraZeneca (United States) (US)
- 1AstraZeneca, Gaithersburg, Maryland.
- 2AstraZeneca, Waltham, Massachusetts.
- 3AstraZeneca, Munich, Germany.
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Oberst, Michael D.
- ORCID
- Pore, Nabendu
- Wu, Song
- Standifer, Nathan
- Jure-Kunkel, Maria
- Shrestha, Yashaswi
- Halpin, Rebecca
- Mulgrew, Kathy
- Martin, Philip
- Meekin, John
- Bisha, Ina
- Proia, Theresa A.
- Miragaia, Ricardo J.
- Herbst, Ronald
- Gupta, Ashok
- Abdullah, Shaad E.
- Raja, Rajiv
- Frigault, Melanie M.
- Barrett, J. Carl
- Ascierto, Maria Libera
- Oberst, Michael D.
- Venue
- Cancer Discovery
- Published
- 2021-07-06
- Volume
- 11
- Issue
- 11
- Pages
- 2828-2845
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W3178510225
- Cited by
- 88
- References
- 47
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 11 · 2023: 16 · 2022: 27 · 2021: 3
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Discovery (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- AstraZeneca (-)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- STK11 mutation, LKB1, non-small cell lung cancer, durvalumab, tremelimumab, PD-L1 blockade, CTLA-4 blockade, immunotherapy resistance, STAT3 signaling, STAT3 knockdown, antisense oligonucleotides, tumor immune phenotype, neutrophils, Th17 cells, myeloid cells, KRAS mutation, immune checkpoint inhibitors
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Retrospective Studies, Protein Serine-Threonine Kinases, STAT3 Transcription Factor, Tumor Microenvironment, B7-H1 Antigen, Antibodies, Monoclonal, Humanized
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