Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer.
Journal
NPJ precision oncology
ISSN: 2397-768X
Titre abrégé: NPJ Precis Oncol
Pays: England
ID NLM: 101708166
Informations de publication
Date de publication:
19 Jul 2022
19 Jul 2022
Historique:
received:
24
09
2021
accepted:
08
06
2022
entrez:
19
7
2022
pubmed:
20
7
2022
medline:
20
7
2022
Statut:
epublish
Résumé
Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study we performed a wide-scale phosphoproteomic mass-spectrometry analysis to explore signaling pathways that lead to resistance toward FGFR1 inhibition in lung cancer cells that display (i) intrinsic, (ii) pharmacologically induced and (iii) mutationally induced resistance. Additionally, we correlated AKT activation to CD44 expression in 175 lung cancer patient samples. We identified a CD44/PAK1/AKT signaling axis as a commonly occurring resistance mechanism to FGFR1 inhibition in lung cancer. Co-inhibition of AKT/FGFR1, CD44/FGFR1 or PAK1/FGFR1 sensitized 'intrinsically resistant' and 'induced-resistant' lung-cancer cells synergetically to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated with AKT activation in SQCLC patients. Collectively, our phosphoproteomic analysis of lung-cancer cells resistant to FGFR1 inhibitor provides a large data library of resistance-associated phosphorylation patterns and leads to the proposal of a common resistance pathway comprising CD44, PAK1 and AKT activation. Examination of CD44/PAK1/AKT activation could help to predict response to FGFR1 inhibition. Moreover, combination between AKT and FGFR1 inhibitors may pave the way for an effective therapy of patients with treatment-resistant FGFR1-dependent lung cancer.
Identifiants
pubmed: 35853934
doi: 10.1038/s41698-022-00296-2
pii: 10.1038/s41698-022-00296-2
pmc: PMC9296622
doi:
Types de publication
Journal Article
Langues
eng
Pagination
52Informations de copyright
© 2022. The Author(s).
Références
Oncotarget. 2018 Jul 31;9(59):31549-31558
pubmed: 30140389
Clin Cancer Res. 2016 Jun 1;22(11):2599-601
pubmed: 26979397
Cancer Med. 2020 May;9(10):3574-3583
pubmed: 32207251
Mod Pathol. 2014 Feb;27(2):214-21
pubmed: 23887299
Mol Cell Biol. 2003 Oct;23(20):7108-21
pubmed: 14517282
Sci Rep. 2016 Oct 07;6:34933
pubmed: 27713506
Ann Oncol. 2019 May 1;30(5):774-780
pubmed: 30860570
Cancer Res. 2010 Jan 15;70(2):440-6
pubmed: 20068163
Cancer Cell. 2017 Apr 10;31(4):549-562.e11
pubmed: 28399410
Oncogenesis. 2016 Jul 18;5(7):e241
pubmed: 27429073
Sci Transl Med. 2010 Dec 15;2(62):62ra93
pubmed: 21160078
Proc Natl Acad Sci U S A. 2016 May 17;113(20):5688-93
pubmed: 27155012
Mol Cancer Ther. 2017 Apr;16(4):614-624
pubmed: 28255027
Cancer Biol Ther. 2016 Aug 2;17(8):813-23
pubmed: 27260988
Clin Cancer Res. 2011 May 1;17(9):2852-62
pubmed: 21536547
Oncol Lett. 2020 Mar;19(3):1999-2004
pubmed: 32194695
J Clin Oncol. 2017 Jan 10;35(2):157-165
pubmed: 27870574
Cancer Chemother Pharmacol. 2016 Apr;77(4):787-95
pubmed: 26931343
J Thorac Oncol. 2019 Oct;14(10):1847-1852
pubmed: 31195180
Mod Pathol. 2012 Nov;25(11):1473-80
pubmed: 22684217
Ann Oncol. 2020 May;31(5):619-625
pubmed: 32205016
Clin Cancer Res. 2017 Sep 15;23(18):5366-5373
pubmed: 28615371
Carcinogenesis. 2017 Oct 26;38(11):1063-1072
pubmed: 28968756
Nature. 2019 Nov;575(7782):299-309
pubmed: 31723286
J Cell Sci. 2012 Apr 1;125(Pt 7):1621-6
pubmed: 22566665
Nature. 2015 Feb 26;518(7540):495-501
pubmed: 25719666
Mol Cell Biol. 2003 Nov;23(22):8058-69
pubmed: 14585966
J Hematol Oncol. 2018 May 10;11(1):64
pubmed: 29747682
Cancer Biol Med. 2015 Mar;12(1):10-22
pubmed: 25859407
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9691-6
pubmed: 15983381
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Cell Death Differ. 2014 Nov;21(11):1687-95
pubmed: 24971484
Am J Hum Genet. 2018 Oct 4;103(4):579-591
pubmed: 30290153
Tumour Biol. 2016 Nov;37(11):14585-14594
pubmed: 27614686
Nat Commun. 2017 Sep 4;8(1):410
pubmed: 28871105
Transl Lung Cancer Res. 2014 Oct;3(5):291-300
pubmed: 25806314
Clin Cancer Res. 2017 Nov 15;23(22):6823-6832
pubmed: 28874413
J Vis Exp. 2009 Jul 21;(29):
pubmed: 19623160
Exp Ther Med. 2017 Nov;14(5):5214-5218
pubmed: 29201239
Oncogene. 2005 Nov 14;24(50):7455-64
pubmed: 16288292
Nat Rev Cancer. 2013 Oct;13(10):714-26
pubmed: 24060863
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Nat Rev Clin Oncol. 2015 Sep;12(9):511-26
pubmed: 25963091
Ann Oncol. 2014 Mar;25(3):552-563
pubmed: 24265351
Cancer Discov. 2019 Jan;9(1):96-113
pubmed: 30361447
J Thorac Oncol. 2012 Dec;7(12):1775-1780
pubmed: 23154548
J Hematol Oncol. 2021 Feb 10;14(1):23
pubmed: 33568192
Oncol Lett. 2016 Mar;11(3):1685-1692
pubmed: 26998062
Mol Cell Biol. 2003 Apr;23(8):2981-90
pubmed: 12665594
Mol Cancer. 2018 Feb 19;17(1):36
pubmed: 29455664
Nat Rev Clin Oncol. 2019 Feb;16(2):105-122
pubmed: 30367139
Clin Cancer Res. 2015 May 15;21(10):2213-20
pubmed: 25979927
Mayo Clin Proc. 2019 Aug;94(8):1623-1640
pubmed: 31378236
Cancer Chemother Pharmacol. 2008 Nov;62(6):949-57
pubmed: 18259754
J Proteome Res. 2016 Jul 1;15(7):2321-6
pubmed: 27297043
J Cell Sci. 2013 Aug 15;126(Pt 16):3515-25
pubmed: 23950111
Cancer Res. 2010 Mar 1;70(5):2085-94
pubmed: 20179196
EMBO Mol Med. 2018 Sep;10(9):
pubmed: 30097507
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Oral Oncol. 2020 Apr;103:104615
pubmed: 32120340
Front Oncol. 2017 Mar 27;7:50
pubmed: 28396848