Cancer Research on Prevention and Treatment    2022, Vol. 49 Issue (08) : 850-854     DOI: 10.3971/j.issn.1000-8578.2022.21.1133
Correlation Between STK11 Gene Mutation and Immunotherapy of Non-small Cell Lung Cancer
XIA Siyu, ZHAO Zitong, LI Li
Medical Oncology Second Ward, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Abstract Lung cancer is one of the most common malignant tumors. Globally, the incidence and mortality of lung cancer are very high and on the rise. In recent years, immune checkpoint inhibitors (ICIs) have a significant survival advantage in treating advanced NSCLC. However, for NSCLC patients with positive driver genes, ICIs are not effective. But some tumor suppressor genes have varying degrees of impact on immunotherapy through mutations or deletions. Among them, serine/threonine kinase 11 (STK11) gene mutations are closely related to PD-1/PD-L1 ICIs. Studies have found that STK11 mutations are related to reduced immune cell infiltration, low PD-L1 expression and poor response to PD-L1 inhibition. This article reviews the research progress of the correlation between STK11 gene mutation and immunotherapy on NSCLC.
Keywords STK11      ICIs      NSCLC      Gene mutation      Immunotherapy     
ZTFLH:  734.2  
Issue Date: 12 August 2022
 Cite this article:   
XIA Siyu,ZHAO Zitong,LI Li. Correlation Between STK11 Gene Mutation and Immunotherapy of Non-small Cell Lung Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 850-854.
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[1] Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021 [J].
CA Cancer J Cin, 2021, 71(1): 7-33.
[2] 王莉新, 吴文斌, 朱诗国. 非小细胞肺癌免疫治疗的策略与展望
[J]. 现代免疫学, 2018, 38(3): 247-251. [Wang LX, Wu WB, Zhu
SG. Strategies and prospects of immunotherapy for non-small cell
lung cancer[J]. Xian Dai Mian Yi Xue, 2018, 38(3): 247-251.]
[3] Gibert J, Clavé S, Hardy-Werbin M, et al. Concomitant genomic
alterations in KRAS mutant advanced lung adenocarcinoma[J].
Lung Cancer, 2020, 140: 42-45.
[4] 陈捷, 姜达, 黄芳. 非小细胞肺癌中驱动基因状态与免疫治疗
相关性的研究进展[J]. 中国肺癌杂志, 2019, 22(4): 233-238.
[Chen J, Jiang D, Huang F. Advances of the Correlation between
Driver Gene Status and Immunotherapy in Non-small Cell Lung
Cancer[J]. Zhongguo Fei Ai Za Zhi, 2019, 22(4): 233-238.]
[5] Zhao N, Wilkerson MD, Shah U, et al. Alterations of LKB1
and KRAS and risk of brain metastasis: comprehensive
characterization by mutation analysis, copy number, and gene
expr‍ession in non-small-cell lung carcinoma[J]. Lung Cancer,
2014, 86(2): 255-261.
[6] Guertin DA, Sabatini DM. Defining the role of mTOR in cancer[J].
Cancer Cell, 2007, 12(1): 9-22.
[7] Hawley SA, Boudeau J, Reid JL, et al. Complexes between the
LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/
beta are upstream kinases in the AMP-activated protein kinase
cascade[J]. J Biol, 2003, 2(4): 28.
[8] Shirwany NA, Zou MH. AMPK: a cellular metabolic and redox
sensor. A minireview[J]. Front Biosci (Landmark Ed), 2014,
19(3): 447-474.
[9] Stein SC, Woods A, Jones NA, et al. The regulation of AMPactivated
protein kinase by phosphorylation[J]. Biochem J, 2000,
345 Pt 3(Pt 3): 437-443.
[10] Hardie DG. AMPK: a target for drugs and natural products with
effects on both diabetes and cancer[J]. Diabetes, 2013, 62(7):
[11] Lizcano JM, G?ransson O, Toth R, et al. LKB1 is a kinase
that activates 13 kinases of the AMPK subfamily, including
MARK/PAR-1[J]. EMBO J, 2004, 23(4): 833-843.
[12] Manning BD, Cantley LC. United at last: the tuberous sclerosis
complex gene products connect the phosphoinositide 3-kinase/Akt
pathway to mammalian target of rapamycin (mTOR) signalling[J].

Biochem Soc Trans, 2003, 31(Pt 3): 573-578.

[13] Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response
to control cell growth and survival[J]. Cell, 2003, 115(5): 577-590.
[14] Wang Z, Wang N, Liu P, et al. AMPK and Cancer[J]. Exp Suppl,
2016, 107: 203-226.
[15] 江美林, 彭文颖, 李佳, 等. 非小细胞肺癌免疫治疗生物标志物
研究进展[J]. 肿瘤防治研究, 2018, 45(10): 805-810. [Jiang ML,
Peng WY, Li J, et al. Research progress in non-small cell lung
cancer immunotherapy biomarkers[J]. Zhong Liu Fang Zhi Yan
Jiu, 2018, 45(10): 805-810.]
[16] Aggarwal C, Thompson JC, Chien AL, et al. Baseline Plasma
Tumor Mutation Burden Predicts Response to Pembrolizumabbased
Therapy in Patients with Metastatic Non-Small Cell Lung
Cancer[J]. Clin Cancer Res, 2020, 26(10): 2354-2361.
[17] Biton J, Mansuet-Lupo A, Pécuchet N, et al. TP53, STK11, and
EGFR Mutations Predict Tumor Immune Profile and the Response
to Anti-PD-1 in Lung Adenocarcinoma[J]. Clin Cancer Res, 2018,
24(22): 5710-5723.
[18] Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1
Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung
Adenocarcinoma[J]. Cancer Discov, 2018, 8(7): 822-835.
[19] Rizvi H, Sanchez-Vega F, La K, et al. Molecular Determinants
of Response to Anti-Programmed Cell Death (PD)-1 and Anti-
Programmed Death-Ligand 1 (PD-L1) Blockade in Patients
With Non-Small-Cell Lung Cancer Profiled With Targeted Next-
Generation Sequencing[J]. J Clin Oncol, 2018, 36(7): 633-641.
[20] Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic
alterations define major subsets of KRAS-mutant lung
adenocarcinoma with distinct biology, immune profiles, and
therapeutic vulnerabilities[J]. Cancer Discov, 2015, 5(8): 860-877.
[21] Skoulidis F, Heymach JV. Co-occurring genomic alterations
in non-small-cell lung cancer biology and therapy[J]. Nat Rev
Cancer, 2019, 19(9): 495-509.
[22] Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden
and Response Rate to PD-1 Inhibition[J]. N Engl J Med, 2017,
377(25): 2500-2501.
[23] Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency
predicts response of solid tumors to PD-1 blockade[J]. Science,
2017, 357(6349): 409-413.
[24] Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in
Stage IV or Recurrent Non-Small-Cell Lung Cancer[J]. N Engl J
Med, 2017, 376(25): 2415-2426.
[25] Binnewies M, Roberts EW, Kersten K, et al. Understanding the
tumor immune microenvironment (TIME) for effective therapy[J].
Nat Med, 2018, 24(5): 541-550.
[26] Topalian SL, Taube JM, Anders RA, et al. Mechanism-driven
biomarkers to guide immune checkpoint blockade in cancer
therapy[J]. Nat Rev Cancer, 2016, 16(5): 275-287.
[27] Donnem T, Kilvaer TK, Andersen S, et al. Strategies for clinical
implementation of TNM-Immunoscore in resected nonsmall-cell
lung cancer[J]. Ann Oncol, 2016, 27(2): 225-232.
[28] Kim HJ, Cantor H. CD4 T-cell subsets and tumor immunity: the
helpful and the not-so-helpful[J]. Cancer Immunol Res, 2014,
2(2): 91-98.
[29] Hiraoka K, Miyamoto M, Cho Y, et al. Concurrent infiltration by
CD8+ T cells and CD4+ T cells is a favourable prognostic factor
in non-small-cell lung carcinoma[J]. Br J Cancer, 2006, 94(2):
[30] Wang H, Guo J, Shang X, et al. Less immune cell infiltration
and worse prognosis after immunotherapy for patients with
lung adenocarcinoma who harbored STK11 mutation[J]. Int
Immunopharmacol, 2020, 84: 106574.
[31] El Osta B, Behera M, Kim S, et al. Characteristics and Outcomes of
Patients With Metastatic KRAS-Mutant Lung Adenocarcinomas:
The Lung Cancer Mutation Consortium Experience[J]. J Thorac
Oncol, 2019, 14(5): 876-889.
[32] La Fleur L, Falk-S?rqvist E, Smeds P, et al. Mutation patterns
in a population-based non-small cell lung cancer cohort and
prognostic impact of concomitant mutations in KRAS and TP53
or STK11[J]. Lung Cancer, 2019, 130: 50-58.
[33] Schabath MB, Welsh EA, Fulp WJ, et al. Differential association
of STK11 and TP53 with KRAS mutation-associated gene
expr‍ession, proliferation and immune surveillance in lung
adenocarcinoma[J]. Oncogene, 2016, 35(24): 3209-3216.
[34] Bange E, Marmarelis ME, Hwang WT, et al. Impact of KRAS
and TP53 Co-Mutations on Outcomes After First-Line Systemic
Therapy Among Patients With STK11-Mutated Advanced
Non-Small-Cell Lung Cancer[J]. JCO Precis Oncol, 2019, 3:
[35] Skoulidis F, Li BT, Dy GK, et al. Sotorasib for Lung Cancers
with KRAS p.G12C Mutation[J]. N Engl J Med, 2021, 384(25):
[36] Romero R, Sayin VI, Davidson SM, et al. Keap1 loss promotes
Kras-driven lung cancer and results in dependence on
glutaminolysis[J]. Nat Med, 2017, 23(11): 1362-1368.
[37] Papillon-Cavanagh S, Doshi P, Dobrin R, et al. STK11 and KEAP1
mutations as prognostic biomarkers in an observational real-world
lung adenocarcinoma cohort[J]. ESMO Open, 2020, 5(2): e000706.
[38] Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated
Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus
Pemetrexed and Platinum for Previously Untreated Metastatic
Nonsquamous Non-Small-Cell Lung Cancer[J]. J Clin Oncol,
2020, 38(14): 1505-1517.
[39] Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus
chemotherapy for previously untreated, PD-L1-expressing,
locally advanced or metastatic non-small-cell lung cancer
(KEYNOTE-042): a randomised, open-label, controlled, phase 3
trial[J]. Lancet,, 2019, 393(10183): 1819-1830.
[40] Armon S, Hofman P, Ilié M. Perspectives and Issues in the
Assessment of SMARCA4 Deficiency in the Management of
Lung Cancer Patients[J]. Cells, 2021, 10(8): 1920.

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