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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.

Publication ,  Journal Article
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 ...
Published in: Cancer Discov
November 2021

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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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

November 2021

Volume

11

Issue

11

Start / End Page

2828 / 2845

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • STAT3 Transcription Factor
  • Retrospective Studies
  • Protein Serine-Threonine Kinases
  • Mutation
  • Lung Neoplasms
  • Humans
  • Carcinoma, Non-Small-Cell Lung
  • B7-H1 Antigen
  • Antibodies, Monoclonal, Humanized
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Pore, N., Wu, S., Standifer, N., Jure-Kunkel, M., de Los Reyes, M., Shrestha, Y., … Oberst, M. D. (2021). 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. Cancer Discov, 11(11), 2828–2845. https://doi.org/10.1158/2159-8290.CD-20-1543
Pore, Nabendu, Song Wu, Nathan Standifer, Maria Jure-Kunkel, Melissa de Los Reyes, Yashaswi Shrestha, Rebecca Halpin, et al. “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.Cancer Discov 11, no. 11 (November 2021): 2828–45. https://doi.org/10.1158/2159-8290.CD-20-1543.
Pore, Nabendu, et al. “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.Cancer Discov, vol. 11, no. 11, Nov. 2021, pp. 2828–45. Pubmed, doi:10.1158/2159-8290.CD-20-1543.
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 TA, Miragaia RJ, Herbst R, Gupta A, Abdullah SE, Raja R, Frigault MM, Barrett JC, Dennis PA, Ascierto ML, Oberst MD. 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. Cancer Discov. 2021 Nov;11(11):2828–2845.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

November 2021

Volume

11

Issue

11

Start / End Page

2828 / 2845

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • STAT3 Transcription Factor
  • Retrospective Studies
  • Protein Serine-Threonine Kinases
  • Mutation
  • Lung Neoplasms
  • Humans
  • Carcinoma, Non-Small-Cell Lung
  • B7-H1 Antigen
  • Antibodies, Monoclonal, Humanized