Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer

Overview

Journal Cancer Discov

Specialty Oncology

Date 2022 Jan 26

PMID 35078784

Authors

Anup Kumar Biswas

Seoyoung Han

Yifan Tai

Wanchao Ma

Courtney Coker

S Aidan Quinn

Ahmad Rushdi Shakri

Timothy James Zhong

Hanna Scholze

Galina G Lagos

Angeliki Mela

Katia Manova-Todorova

Elisa de Stanchina

Adolfo A Ferrando

Cathy Mendelsohn

Peter Canoll

Helena A Yu

Paul K Paik

Anjali Saqi

Catherine A Shu

Mark G Kris

Joan Massague

Swarnali Acharyya

Affiliations

Soon will be listed here.

Abstract

Significance: Treatment with the EGFR TKI osimertinib prolongs the survival of patients with EGFR-mutant lung cancer; however, patients develop metastatic relapses, often to the brain. We identified a novel intracellular S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and can be targeted by pan-RAR antagonists to prevent cancer progression and prolong patient survival. This article is highlighted in the In This Issue feature, p. 873.

Citing Articles

RBM10 deficiency promotes brain metastasis by modulating sphingolipid metabolism in a BBB model of EGFR mutant lung adenocarcinoma.

Xu G, An B, Wang R, Pan B, Hao H, Ren X J Exp Clin Cancer Res. 2025; 44(1):95.

PMID: 40069781 PMC: 11895392. DOI: 10.1186/s13046-025-03347-1.

Cancer brain metastasis: molecular mechanisms and therapeutic strategies.

Lu Y, Huang Y, Zhu C, Li Z, Zhang B, Sheng H Mol Biomed. 2025; 6(1):12.

PMID: 39998776 PMC: 11861501. DOI: 10.1186/s43556-025-00251-0.

The Significance of Aldehyde Dehydrogenase 1 in Cancers.

Nguyen A, Facey C, Boman B Int J Mol Sci. 2025; 26(1.

PMID: 39796106 PMC: 11720537. DOI: 10.3390/ijms26010251.

Risk factors for brain metastasis in lung cancer: an umbrella review of systematic reviews and meta-analyses.

Wan X, Mo H, Chen J, Zhou Q, Qiu S, Zou Y BMJ Open. 2025; 15(1):e087181.

PMID: 39773793 PMC: 11749772. DOI: 10.1136/bmjopen-2024-087181.

Regulation of metastatic organotropism.

Dunbar K, Efe G, Cunningham K, Esquea E, Navaridas R, Rustgi A Trends Cancer. 2024; 11(3):216-231.

PMID: 39732596 PMC: 11903188. DOI: 10.1016/j.trecan.2024.11.012.

References

Gilbert L, Hemann M . DNA damage-mediated induction of a chemoresistant niche. Cell. 2010; 143(3):355-66. PMC: 2972353. DOI: 10.1016/j.cell.2010.09.043. View

Piotrowska Z, Isozaki H, Lennerz J, Gainor J, Lennes I, Zhu V . Landscape of Acquired Resistance to Osimertinib in -Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired Fusion. Cancer Discov. 2018; 8(12):1529-1539. PMC: 6279502. DOI: 10.1158/2159-8290.CD-18-1022. View

Ramalingam S, Vansteenkiste J, Planchard D, Cho B, Gray J, Ohe Y . Overall Survival with Osimertinib in Untreated, -Mutated Advanced NSCLC. N Engl J Med. 2019; 382(1):41-50. DOI: 10.1056/NEJMoa1913662. View

Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C . Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009; 361(10):958-67. DOI: 10.1056/NEJMoa0904554. View

Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G . S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res. 2011; 9(2):133-48. PMC: 3078037. DOI: 10.1158/1541-7786.MCR-10-0394. View

Tang X, Gudas L . Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2010; 6:345-64. DOI: 10.1146/annurev-pathol-011110-130303. View

Midha A, Dearden S, McCormack R . EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015; 5(9):2892-911. PMC: 4633915. View

Carlson P, Dasgupta A, Grzelak C, Kim J, Barrett A, Coleman I . Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat Cell Biol. 2019; 21(2):238-250. PMC: 6948102. DOI: 10.1038/s41556-018-0267-0. View

Ge M, Zhuang Y, Zhou X, Huang R, Liang X, Zhan Q . High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases. J Neurooncol. 2017; 135(2):413-418. DOI: 10.1007/s11060-017-2590-x. View

10.

Rangachari D, Yamaguchi N, VanderLaan P, Folch E, Mahadevan A, Floyd S . Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015; 88(1):108-11. PMC: 4355240. DOI: 10.1016/j.lungcan.2015.01.020. View

11.

Singh Achrol A, Rennert R, Anders C, Soffietti R, Ahluwalia M, Nayak L . Brain metastases. Nat Rev Dis Primers. 2019; 5(1):5. DOI: 10.1038/s41572-018-0055-y. View

12.

Bresnick A, Weber D, Zimmer D . S100 proteins in cancer. Nat Rev Cancer. 2015; 15(2):96-109. PMC: 4369764. DOI: 10.1038/nrc3893. View

13.

Hobbs J, May R, Tanousis K, McNeill E, Mathies M, Gebhardt C . Myeloid cell function in MRP-14 (S100A9) null mice. Mol Cell Biol. 2003; 23(7):2564-76. PMC: 150714. DOI: 10.1128/MCB.23.7.2564-2576.2003. View

14.

Maloney C, Edelman M, Kallis M, Soffer S, Symons M, Steinberg B . Intratibial Injection Causes Direct Pulmonary Seeding of Osteosarcoma Cells and Is Not a Spontaneous Model of Metastasis: A Mouse Osteosarcoma Model. Clin Orthop Relat Res. 2018; 476(7):1514-1522. PMC: 6437576. DOI: 10.1007/s11999.0000000000000291. View

15.

Cross D, Ashton S, Ghiorghiu S, Eberlein C, Nebhan C, Spitzler P . AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014; 4(9):1046-61. PMC: 4315625. DOI: 10.1158/2159-8290.CD-14-0337. View

16.

Song R, Struhl K . S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation. Sci Adv. 2021; 7(1). PMC: 7775746. DOI: 10.1126/sciadv.abe5357. View

17.

Shin D, Na I, Kim C, Park S, Baek H, Yang S . EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014; 9(2):195-9. DOI: 10.1097/JTO.0000000000000069. View

18.

Ballard P, Yates J, Yang Z, Kim D, Yang J, Cantarini M . Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016; 22(20):5130-5140. DOI: 10.1158/1078-0432.CCR-16-0399. View

19.

Bos P, Nguyen D, Massague J . Modeling metastasis in the mouse. Curr Opin Pharmacol. 2010; 10(5):571-7. PMC: 2952835. DOI: 10.1016/j.coph.2010.06.003. View

20.

Yu H, Tian S, Drilon A, Borsu L, Riely G, Arcila M . Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA Oncol. 2015; 1(7):982-4. PMC: 4665629. DOI: 10.1001/jamaoncol.2015.1066. View