CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.
ATC
CDK4 Thr172-phosphorylation
PDTC
biomarkers
dabrafenib
palbociclib
trametinib
Journal
Frontiers in endocrinology
ISSN: 1664-2392
Titre abrégé: Front Endocrinol (Lausanne)
Pays: Switzerland
ID NLM: 101555782
Informations de publication
Date de publication:
2023
2023
Historique:
received:
26
06
2023
accepted:
26
09
2023
medline:
15
11
2023
pubmed:
15
11
2023
entrez:
15
11
2023
Statut:
epublish
Résumé
CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers. We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays. CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16 Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.
Sections du résumé
Background
UNASSIGNED
CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers.
Methods
UNASSIGNED
We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays.
Results
UNASSIGNED
CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16
Conclusion
UNASSIGNED
Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.
Identifiants
pubmed: 37964967
doi: 10.3389/fendo.2023.1247542
pmc: PMC10641312
doi:
Banques de données
figshare
['10.6084/m9.figshare.24278626']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1247542Informations de copyright
Copyright © 2023 Pita, Raspé, Coulonval, Decaussin-Petrucci, Tarabichi, Dom, Libert, Craciun, Andry, Wicquart, Leteurtre, Trésallet, Marlow, Copland, Durante, Maenhaut, Cavaco, Dumont, Costante and Roger.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Oncogene. 2008 Mar 6;27(11):1554-61
pubmed: 17873908
J Clin Oncol. 2017 Sep 1;35(25):2875-2884
pubmed: 28580882
Cancer Cell. 2018 Jul 9;34(1):9-20
pubmed: 29731395
PLoS Genet. 2016 Aug 05;12(8):e1006239
pubmed: 27494611
Pathol Res Pract. 2003;199(6):399-404
pubmed: 12924440
Cell. 2014 Oct 23;159(3):676-90
pubmed: 25417114
Cancer Cell. 2010 Jul 13;18(1):63-73
pubmed: 20609353
Mol Cell Biol. 2006 Jul;26(13):5070-85
pubmed: 16782892
Tumour Biol. 2016 Mar;37(3):3359-64
pubmed: 26446458
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4171-6
pubmed: 19237555
Clin Cancer Res. 2018 Jul 1;24(13):3059-3068
pubmed: 29615459
Endocr Pathol. 2022 Mar;33(1):27-63
pubmed: 35288841
Mod Pathol. 2021 Jan;34(1):32-41
pubmed: 32719445
Cell Rep. 2021 Apr 6;35(1):108944
pubmed: 33826903
Endocr Relat Cancer. 2011 Dec 01;18(6):743-57
pubmed: 21937739
J Clin Invest. 2016 Mar 1;126(3):1052-66
pubmed: 26878173
Science. 2022 Jan 14;375(6577):eabc1495
pubmed: 35025636
Science. 2018 Dec 21;362(6421):1416-1422
pubmed: 30573629
Thyroid. 2019 Aug;29(8):1036-1043
pubmed: 31319771
Thyroid. 2000 Sep;10(9):741-6
pubmed: 11041450
Oncogene. 2020 Jul;39(29):5165-5176
pubmed: 32541838
Eur J Endocrinol. 2023 Jan 10;188(1):
pubmed: 36651156
Hum Mol Genet. 2015 Apr 15;24(8):2318-29
pubmed: 25576899
Thyroid. 2018 Jul;28(7):945-951
pubmed: 29742974
N Engl J Med. 2016 Nov 3;375(18):1738-1748
pubmed: 27717303
Br J Cancer. 2006 Dec 18;95(12):1670-7
pubmed: 17117177
Oncotarget. 2015 Dec 15;6(40):42445-67
pubmed: 26636651
Oncotarget. 2015 Oct 27;6(33):34629-48
pubmed: 26431489
Cancer Med. 2021 Sep;10(17):5748-5756
pubmed: 34405547
Expert Rev Anticancer Ther. 2019 Jul;19(7):569-587
pubmed: 31219365
Oncotarget. 2018 Jul 24;9(57):30940-30941
pubmed: 30123416
Nat Commun. 2022 Sep 7;13(1):5258
pubmed: 36071033
Mol Cell Biol. 2009 Nov;29(21):5657-70
pubmed: 19720745
Lancet Oncol. 2012 Aug;13(8):773-81
pubmed: 22805291
J Biol Chem. 2003 Jul 18;278(29):26533-40
pubmed: 12730225
J Clin Endocrinol Metab. 2010 Dec;95(12):5338-47
pubmed: 20810568
Eur Thyroid J. 2022 Dec 22;12(1):
pubmed: 36377723
Mol Endocrinol. 2006 Dec;20(12):3279-92
pubmed: 16916940
Mol Cell Biol. 2000 Aug;20(15):5690-9
pubmed: 10891505
Curr Opin Oncol. 2023 Jan 1;35(1):1-9
pubmed: 36398690
Endocr Relat Cancer. 2009 Mar;16(1):17-44
pubmed: 18987168
Cell Div. 2006 Nov 08;1:25
pubmed: 17092340
Cancer Biol Ther. 2012 Jul;13(9):776-81
pubmed: 22688732
Mol Biol Cell. 2008 Nov;19(11):4814-25
pubmed: 18799615
Cancer Res. 2007 Nov 1;67(21):10148-58
pubmed: 17981789
Genes Dev. 1999 Jun 15;13(12):1501-12
pubmed: 10385618
Endocr Pathol. 2008 Fall;19(3):184-9
pubmed: 18766473
Ann Surg Oncol. 2007 May;14(5):1772-9
pubmed: 17195959
Exp Cell Res. 2003 Nov 15;291(1):135-49
pubmed: 14597415
J Clin Invest. 2007 Jan;117(1):218-28
pubmed: 17160137
Clin Cancer Res. 2019 May 15;25(10):3141-3151
pubmed: 30737244
Cancer. 2023 Apr 1;129(7):1051-1063
pubmed: 36760031
Mol Cell Biol. 2009 Aug;29(15):4188-200
pubmed: 19487459
Ann Surg Oncol. 2008 Oct;15(10):2811-26
pubmed: 18612701
Sci Rep. 2018 Feb 13;8(1):2918
pubmed: 29440769
Oncotarget. 2017 Dec 23;9(13):10905-10919
pubmed: 29541385
J Oncol. 2011;2011:542358
pubmed: 21772843
J Endocrinol Invest. 2019 May;42(5):527-540
pubmed: 30191474
Eur Thyroid J. 2019 Oct;8(5):227-245
pubmed: 31768334
Clin Cancer Res. 2014 Sep 1;20(17):4449-58
pubmed: 24958809
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Adv Enzyme Regul. 1984;22:27-55
pubmed: 6382953
Cell. 2020 Apr 16;181(2):424-441.e21
pubmed: 32234521
Cancer Discov. 2021 Oct;11(10):2582-2601
pubmed: 33990344
J Cell Biol. 1992 Apr;117(2):383-93
pubmed: 1313816
Nat Commun. 2019 Jun 24;10(1):2764
pubmed: 31235699
Trends Cancer. 2017 Jan;3(1):39-55
pubmed: 28303264
Cancer Discov. 2016 Jul;6(7):740-53
pubmed: 27217383
Mol Cell Biol. 1994 Apr;14(4):2713-21
pubmed: 8139570
Mol Biol Cell. 2011 Nov;22(21):3971-85
pubmed: 21900495
Thyroid. 2018 Jan;28(1):79-87
pubmed: 29161986
J Cell Sci. 2012 Sep 15;125(Pt 18):4253-63
pubmed: 22718346
Int J Cancer. 1998 Jun 10;76(6):806-11
pubmed: 9626345
Curr Opin Oncol. 2021 Jan;33(1):3-8
pubmed: 33060402
Endocr Relat Cancer. 2019 Jan 1;26(4):425-436
pubmed: 30699064
J Clin Endocrinol Metab. 2006 Aug;91(8):2892-9
pubmed: 16684830
Oncogene. 2010 Jul 15;29(28):4018-32
pubmed: 20473330
Eur J Cancer. 2007 Jan;43(1):194-201
pubmed: 17046239
J Clin Endocrinol Metab. 2008 Nov;93(11):4331-41
pubmed: 18713817
Cancer Discov. 2018 Feb;8(2):216-233
pubmed: 29101163
Cell Cycle. 2014;13(18):2879-88
pubmed: 25486476
Biostatistics. 2004 Oct;5(4):557-72
pubmed: 15475419
Endocr Relat Cancer. 2003 Jun;10(2):179-86
pubmed: 12790780
PLoS Genet. 2013 May;9(5):e1003546
pubmed: 23737759
J Biol Chem. 2003 Dec 26;278(52):52052-60
pubmed: 14551212
Cell Cycle. 2006 Jan;5(1):61-70
pubmed: 16294008
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4166-70
pubmed: 19237565
Am J Surg Pathol. 2007 Aug;31(8):1256-64
pubmed: 17667551
J Clin Oncol. 2018 Jan 1;36(1):7-13
pubmed: 29072975
N Engl J Med. 2016 Nov 17;375(20):1925-1936
pubmed: 27959613
Br J Clin Pharmacol. 2014 Sep;78(3):524-32
pubmed: 24606567
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Cell Rep. 2018 Mar 13;22(11):2978-2994
pubmed: 29539425
J Clin Endocrinol Metab. 2014 Mar;99(3):E497-507
pubmed: 24423316
Nat Med. 2012 Oct;18(10):1503-10
pubmed: 22983396
Cell Cycle. 2011 Aug 1;10(15):2497-503
pubmed: 21775818
Pharmacol Rev. 2006 Sep;58(3):621-81
pubmed: 16968952
J Immunother Cancer. 2018 Jul 11;6(1):68
pubmed: 29996921
Cell Cycle. 2007 Nov 15;6(22):2817-25
pubmed: 18032931
Cell Cycle. 2010 Feb 15;9(4):689-99
pubmed: 20107323
Nat Rev Endocrinol. 2017 Nov;13(11):644-660
pubmed: 28707679
Cancer Res. 2009 Jun 1;69(11):4577-81
pubmed: 19458076
Oncogene. 2017 Jul 27;36(30):4349-4361
pubmed: 28368408
Br J Cancer. 2009 Nov 17;101(10):1782-91
pubmed: 19809427
Thyroid. 2016 Jan;26(1):1-133
pubmed: 26462967
Cancer Lett. 2018 Mar 28;417:131-140
pubmed: 29306020
EMBO Mol Med. 2017 Aug;9(8):1052-1066
pubmed: 28566333
Mol Cell Endocrinol. 2018 Jan 15;460:24-35
pubmed: 28652169
Thyroid. 2021 Mar;31(3):337-386
pubmed: 33728999
World J Surg. 2007 May;31(5):934-45
pubmed: 17431717
Nat Rev Cancer. 2022 Jun;22(6):356-372
pubmed: 35304604
Endocr Relat Cancer. 2008 Sep;15(3):801-15
pubmed: 18753363
Ann Oncol. 2022 Jul;33(7):674-684
pubmed: 35491008
Oncogene. 2019 May;38(18):3355-3370
pubmed: 30696953
Nat Rev Mol Cell Biol. 2006 Sep;7(9):667-77
pubmed: 16921403
Nat Rev Cancer. 2011 Jul 07;11(8):558-72
pubmed: 21734724
PLoS One. 2012;7(10):e37807
pubmed: 23115614
Am J Transl Res. 2019 Sep 15;11(9):5888-5896
pubmed: 31632557
Mol Oncol. 2022 Nov 30;:
pubmed: 36453028
Sci Transl Med. 2017 Apr 26;9(387):
pubmed: 28446688
Cell Cycle. 2022 Jan;21(1):12-32
pubmed: 34913830