Targeting S100A9–ALDH1A1–retinoic acid signaling to suppress brain relapse in EGFR-mutant lung cancer Journal Article

   


Authors: Biswas, A. K.; Han, S.; Tai, Y.; Ma, W.; Coker, C.; Quinn, S. A.; Shakri, A. R.; Zhong, T. J.; Scholze, H.; Lagos, G. G.; Mela, A.; Manova-Todorova, K.; de Stanchina, E.; Ferrando, A. A.; Mendelsohn, C.; Canoll, P.; Yu, H. A.; Paik, P. K.; Saqi, A.; Shu, C. A.; Kris, M. G.; Massague, J.; Acharyya, S.
Article Title: Targeting S100A9–ALDH1A1–retinoic acid signaling to suppress brain relapse in EGFR-mutant lung cancer
Abstract: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has significantly prolonged progression-free survival (PFS) in patients with EGFR-mutant lung cancer, including those with brain metastases. However, despite striking ini-tial responses, osimertinib-treated patients eventually develop lethal metastatic relapse, often to the brain. Although osimertinib-refractory brain relapse is a major clinical challenge, its underlying mechanisms remain poorly understood. Using metastatic models of EGFR-mutant lung cancer, we show that cancer cells expressing high intracellular S100A9 escape osimertinib and initiate brain relapses. Mechanistically, S100A9 upregulates ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. We demonstrate that the genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) in cancer cells, or treatment with a pan-RAR antagonist, dramatically reduces brain metastasis. Importantly, S100A9 expression in cancer cells correlates with poor PFS in osimertinib-treated patients. Our study, therefore, identifies a novel, therapeutically targ-etable S100A9–ALDH1A1–RA axis that drives brain relapse. 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. © 2022 The Authors; Published by the American Association for Cancer Research.
Keywords: signal transduction; genetics; mutation; neoplasm recurrence, local; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; pathology; protein kinase inhibitors; lung tumor; brain; tumor recurrence; aniline compounds; retinoic acid; egfr protein, human; non small cell lung cancer; tretinoin; aniline derivative; retinal dehydrogenase; erbb receptors; humans; human; aldh1a1 protein, human; aldehyde dehydrogenase 1 family
Journal Title: Cancer Discovery
Volume: 12
Issue: 4
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2022-04-01
Start Page: 1002
End Page: 1021
Language: English
DOI: 10.1158/2159-8290.Cd-21-0910
PUBMED: 35078784
PROVIDER: scopus
PMCID: PMC8983473
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85128161290&doi=10.1158%2f2159-8290.CD-21-0910&partnerID=40&md5=cb4c560e8944eade339d2e538f0412b8
Notes: Article -- Export Date: 2 May 2022 -- Source: Scopus
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MSK Authors
  1. Helena Alexandra Yu
    283 Yu
  2. Paul K Paik
    255 Paik
  3. Joan Massague
    389 Massague
  4. Katia O Manova-Todorova
    161 Manova-Todorova
  5. Elisa De Stanchina
    347 De Stanchina
  6. Mark Kris
    869 Kris
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