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03 15, 2023;9 (11): eadd3243.

HDAC3 is critical in tumor development and therapeutic resistance in -mutant non-small cell lung cancer.

Lillian J Eichner, Stephanie D Curtis, Sonja N Brun, Caroline K McGuire, Irena Gushterova, Joshua T Baumgart, Elijah Trefts, Debbie S Ross, Tammy J Rymoff, Reuben J Shaw
Author Information
  1. Lillian J Eichner: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA. ORCID
  2. Stephanie D Curtis: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA. ORCID
  3. Sonja N Brun: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA.
  4. Caroline K McGuire: Department of Biochemistry and Molecular Genetics, Northwestern University, 303 E. Superior Street, Chicago, IL USA.
  5. Irena Gushterova: Department of Biochemistry and Molecular Genetics, Northwestern University, 303 E. Superior Street, Chicago, IL USA. ORCID
  6. Joshua T Baumgart: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA. ORCID
  7. Elijah Trefts: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA. ORCID
  8. Debbie S Ross: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA.
  9. Tammy J Rymoff: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA.
  10. Reuben J Shaw: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA USA. ORCID
PMID: 36930718 DOI: 10.1126/sciadv.add3243

Abstract

HDAC3 is one of the main targets of histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. We identified a critical role for HDAC3 in -mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical previously unidentified target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as -mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the GEMM.

References

  1. Clin Cancer Res. 2017 Jun 15;23(12):3139-3149 [PMID: 27986747]
  2. Cell. 2020 Jul 23;182(2):297-316.e27 [PMID: 32619424]
  3. Nature. 2011 May 5;473(7345):101-4 [PMID: 21471965]
  4. Cancer Cell. 2020 May 11;37(5):705-719.e6 [PMID: 32243838]
  5. Clin Cancer Res. 2013 Nov 15;19(22):6183-92 [PMID: 24045185]
  6. Nat Med. 2016 Oct;22(10):1108-1119 [PMID: 27643638]
  7. Cell Stem Cell. 2020 Oct 1;27(4):663-678.e8 [PMID: 32891189]
  8. Clin Cancer Res. 2019 Sep 15;25(18):5686-5701 [PMID: 31227503]
  9. Nature. 2014 Dec 18;516(7531):428-31 [PMID: 25337879]
  10. Nature. 2020 Mar;579(7798):284-290 [PMID: 32103175]
  11. Nat Rev Drug Discov. 2014 Sep;13(9):673-91 [PMID: 25131830]
  12. Cell Mol Biol (Noisy-le-grand). 2005 Oct 24;Suppl 51:OL785-99 [PMID: 16405855]
  13. Cancer Discov. 2020 Mar;10(3):440-459 [PMID: 31915197]
  14. Clin Cancer Res. 2017 Sep 1;23(17):5187-5201 [PMID: 28698201]
  15. Bioinformatics. 2004 Jun 12;20(9):1453-4 [PMID: 14871861]
  16. Nat Rev Cancer. 2017 May;17(5):318-332 [PMID: 28303906]
  17. Nat Rev Clin Oncol. 2020 Feb;17(2):91-107 [PMID: 31570827]
  18. Cancer Res. 2007 Jul 1;67(13):6007-11 [PMID: 17616654]
  19. Trends Endocrinol Metab. 2013 Jan;24(1):48-57 [PMID: 23062770]
  20. Nature. 2017 Jun 22;546(7659):544-548 [PMID: 28614293]
  21. Cancer Discov. 2017 Aug;7(8):852-867 [PMID: 28408401]
  22. Science. 2018 Dec 21;362(6421):1416-1422 [PMID: 30573629]
  23. Cancer Cell. 2013 Feb 11;23(2):143-58 [PMID: 23352126]
  24. EMBO J. 2004 Feb 25;23(4):833-43 [PMID: 14976552]
  25. Cancer Cell. 2013 Jun 10;23(6):718-23 [PMID: 23763999]
  26. Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):E5625-E5634 [PMID: 28652369]
  27. J Clin Invest. 2014 Jan;124(1):30-9 [PMID: 24382387]
  28. Cancer Cell. 2003 Jul;4(1):13-8 [PMID: 12892709]
  29. Biochem J. 2021 Apr 16;478(7):1377-1397 [PMID: 33861845]
  30. Cell Metab. 2019 Feb 5;29(2):285-302.e7 [PMID: 30415923]
  31. Nat Med. 2012 Jun;18(6):934-42 [PMID: 22561686]
  32. Nat Rev Cancer. 2019 Sep;19(9):495-509 [PMID: 31406302]
  33. Nat Commun. 2021 Aug 27;12(1):5155 [PMID: 34453044]
  34. Nat Genet. 2016 Jun;48(6):607-16 [PMID: 27158780]
  35. J Clin Oncol. 2009 Jan 10;27(2):271-8 [PMID: 19064983]
  36. Cancer Cell. 2020 Jun 8;37(6):834-849.e13 [PMID: 32442403]
  37. Bioinformatics. 2004 Nov 22;20(17):3246-8 [PMID: 15180930]
  38. Elife. 2021 Apr 06;10: [PMID: 33821796]
  39. Nature. 2008 Oct 23;455(7216):1069-75 [PMID: 18948947]
  40. Mol Cell. 2013 Dec 26;52(6):769-82 [PMID: 24268577]
  41. Nature. 2014 Oct 9;514(7521):247-51 [PMID: 25119042]
  42. Cancer Immunol Res. 2018 Dec;6(12):1561-1577 [PMID: 30341213]
  43. PLoS One. 2012;7(1):e30815 [PMID: 22303460]
  44. Nat Protoc. 2009;4(7):1064-72 [PMID: 19561589]
  45. Dev Cell. 2016 Feb 8;36(3):316-30 [PMID: 26859354]
  46. Cell. 2018 May 31;173(6):1413-1425.e14 [PMID: 29754815]
  47. Sci Rep. 2017 Dec 4;7(1):16878 [PMID: 29203879]
  48. Immunity. 2018 Oct 16;49(4):764-779.e9 [PMID: 30332632]
  49. Genes Dev. 2013 Jan 15;27(2):197-210 [PMID: 23322301]
  50. Oncogene. 2008 Jun 5;27(25):3635-40 [PMID: 18212743]
  51. Cancer Discov. 2017 Dec;7(12):1450-1463 [PMID: 28963352]
  52. J Clin Invest. 2021 Aug 16;131(16): [PMID: 34396985]
  53. Nature. 2016 Jun 30;534(7609):647-51 [PMID: 27338794]
  54. J Thorac Oncol. 2016 Jun;11(6):838-49 [PMID: 26917230]
  55. Cancer Cell. 2010 Nov 16;18(5):436-47 [PMID: 21075309]
  56. Cancer Discov. 2012 May;2(5):401-4 [PMID: 22588877]
  57. EMBO J. 2008 Apr 9;27(7):1017-28 [PMID: 18354499]
  58. Development. 1991 Dec;113(4):1093-104 [PMID: 1811929]
  59. J Thorac Oncol. 2014 Jun;9(6):794-804 [PMID: 24828662]
  60. Cells. 2019 Jun 18;8(6): [PMID: 31216761]
  61. Cancer Discov. 2017 Jan;7(1):38-53 [PMID: 27733359]
  62. Nat Rev Mol Cell Biol. 2019 Feb;20(2):102-115 [PMID: 30390028]
  63. Cell. 2017 Nov 30;171(6):1284-1300.e21 [PMID: 29195073]
  64. Br J Cancer. 2016 Mar 15;114(6):605-11 [PMID: 26908329]
  65. Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):15090-15095 [PMID: 27956629]
  66. Cancer Discov. 2019 Nov;9(11):1590-1605 [PMID: 31350327]
  67. Mol Cell. 2010 May 28;38(4):576-89 [PMID: 20513432]
  68. Cell. 2017 Feb 9;168(4):629-643 [PMID: 28187285]
  69. Bioinformatics. 2013 Jan 1;29(1):15-21 [PMID: 23104886]
  70. Nat Rev Endocrinol. 2015 Jan;11(1):29-42 [PMID: 25350068]
  71. EMBO J. 1990 Nov;9(11):3631-9 [PMID: 1976511]
  72. Nat Rev Cancer. 2006 Aug;6(8):593-602 [PMID: 16862190]
  73. Mol Cell. 2013 Apr 25;50(2):185-99 [PMID: 23523371]
  74. Oncogene. 2007 Aug 13;26(37):5450-67 [PMID: 17694086]
  75. Cancer Res. 2002 Jul 1;62(13):3659-62 [PMID: 12097271]
  76. Pediatr Blood Cancer. 2019 Aug;66(8):e27820 [PMID: 31099166]
  77. J Clin Invest. 2012 Dec;122(12):4388-400 [PMID: 23143308]
  78. Cancer Discov. 2016 Jun;6(6):612-29 [PMID: 27099234]
  79. Genes Dev. 2014 Jul 15;28(14):1578-91 [PMID: 25030697]
  80. Sci Signal. 2013 Apr 02;6(269):pl1 [PMID: 23550210]
  81. Cancer Discov. 2019 Apr;9(4):526-545 [PMID: 30709805]
  82. Mol Cell. 2014 Jun 5;54(5):728-36 [PMID: 24905006]
  83. Cancer Discov. 2019 Nov;9(11):1606-1627 [PMID: 31350328]
  84. Elife. 2019 Jan 18;8: [PMID: 30657451]
  85. Dev Biol. 1996 Sep 15;178(2):203-16 [PMID: 8812123]
  86. Mol Cell Biol. 2001 Sep;21(18):6091-101 [PMID: 11509652]

Grants

  1. P01 CA120964/NCI NIH HHS
  2. T32 CA009370/NCI NIH HHS
  3. F32 CA206400/NCI NIH HHS
  4. R35 CA220538/NCI NIH HHS
  5. P30 CA023100/NCI NIH HHS
  6. K22 CA251636/NCI NIH HHS
  7. P30 CA014195/NCI NIH HHS

MeSH Term

Animals
Mice
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Drug Resistance, Neoplasm
Lung Neoplasms
Pyridines
Histone Deacetylases

Chemicals

entinostat
Pyridines
histone deacetylase 3
Histone Deacetylases
Journal Article

Links to CNCB-NGDC Resources

GEN: GEND000554 (HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq trametinib entinostat treatment])
GEN: GEND000555 (HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq HDAC3 KO p65 KO])
GEN: GEND000556 (HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq HDAC3 KO p65 KO])
GEN: GEND000557 (HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq HDAC3 KO NKX2-1 KO])

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