title: Loss of PI(4,5)P2 5-Phosphatase A Contributes to Resistance of Human Melanoma Cells to RAF/MEK Inhibitors.
abstract: Past studies have shown that the inositol polyphosphate 5-phosphatase, phosphatidylinositol 4,5-bisphosphate 5-phosphatase (PIB5PA), is commonly downregulated or lost in melanomas, which contributes to elevated activation of phosphatidylinositol 3-kinase (PI3K)/Akt in melanoma cells. In this report, we provide evidence that PIB5PA deficiency plays a role in resistance of melanoma cells to RAF/mitogen-activated protein kinase kinase (MEK) inhibitors. Ectopic expression of PIB5PA enhanced apoptosis induced by the RAF inhibitor PLX4720 in BRAF(V600E) and by the MEK inhibitor U0126 in both BRAF(V600E) and wild-type BRAF melanoma cells. This was due to inhibition of PI3K/Akt, as co-introduction of an active form of Akt (myr-Akt) abolished the effect of overexpression of PIB5PA on apoptosis induced by PLX4720 or U0126. While overexpression of PIB5PA triggered activation of Bad and down-regulation of Mcl-1, knockdown of Bad or overexpression of Mcl-1 recapitulated, at least in part, the effect of myr-Akt, suggesting that regulation of Bad and Mcl-1 is involved in PIB5PA-mediated sensitization of melanoma cells to the inhibitors. The role of PIB5PA deficiency in BRAF inhibitor resistance was confirmed by knockdown of PIB5PA, which led to increased growth of BRAF(V600E) melanoma cells selected for resistance to PLX4720. Consistent with its role in vitro, overexpression of PIB5PA and the MEK inhibitor selumetinib cooperatively inhibited melanoma tumor growth in a xenograft model. Taken together, these results identify loss of PIB5PA as a novel resistance mechanism of melanoma to RAF/MEK inhibitors and suggest that restoration of PIB5PA may be a useful strategy to improve the therapeutic efficacy of the inhibitors in the treatment of melanoma.
authors.affiliation: Department of Immunology, Anhui Medical University, Anhui, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Wang Lai
authors.initials: WL
authors.lastname: Hu
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Tseng
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Lin Jie
authors.initials: LJ
authors.lastname: Zhang
authors.forename: Sen
authors.initials: S
authors.lastname: Yang
references.citation: Cell Death Dis. 2010 Sep 02;1:e69
references.pmid: 21364673
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):256-61
references.pmid: 19303758
references.citation: J Biol Chem. 2002 Feb 22;277(8):6266-72
references.pmid: 11706019
references.citation: Mol Cell. 2005 Apr 1;18(1):13-24
references.pmid: 15808505
references.citation: Cancer Cell. 2009 Aug 4;16(2):115-25
references.pmid: 19647222
references.citation: Clin Cancer Res. 2012 Apr 15;18(8):2316-25
references.pmid: 22261800
references.citation: Nature. 2010 Dec 16;468(7326):973-7
references.pmid: 21107323
references.citation: N Engl J Med. 2011 Jun 30;364(26):2507-16
references.pmid: 21639808
references.citation: Cancer Res. 2011 Feb 1;71(3):629-33
references.pmid: 21266353
references.citation: J Biol Chem. 1999 Apr 16;274(16):10669-72
references.pmid: 10196133
references.citation: J Invest Dermatol. 2010 Jan;130(1):28-37
references.pmid: 19571822
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6
references.pmid: 19915144
references.citation: Clin Chem. 2008 Apr;54(4):757-60
references.pmid: 18375489
references.citation: Nat Rev Clin Oncol. 2011 May 24;8(7):426-33
references.pmid: 21606968
references.citation: N Engl J Med. 2012 Nov;367(18):1694-703
references.pmid: 23020132
references.citation: Lancet Oncol. 2012 Aug;13(8):773-81
references.pmid: 22805291
references.citation: J Clin Oncol. 2010 Feb 20;28(6):1075-83
references.pmid: 20085938
references.citation: Cell. 1997 Oct 17;91(2):231-41
references.pmid: 9346240
references.citation: Nature. 2011 Nov 23;480(7377):387-90
references.pmid: 22113612
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4934-42
references.pmid: 17652623
references.citation: Mol Biol Cell. 2006 Feb;17(2):607-22
references.pmid: 16280363
references.citation: Cell. 2007 Nov 16;131(4):682-93
references.pmid: 18022363
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Oncogene. 2011 Aug 25;30(34):3716-26
references.pmid: 21423203
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22231-6
references.pmid: 21127264
references.citation: J Biol Chem. 2001 Feb 16;276(7):4781-7
references.pmid: 11087761
references.citation: J Biol Chem. 2001 Feb 16;276(7):5339-45
references.pmid: 11087733
references.citation: Nature. 2010 Dec 16;468(7326):968-72
references.pmid: 21107320
references.citation: Nat Rev Drug Discov. 2012 Nov;11(11):873-86
references.pmid: 23060265
references.citation: N Engl J Med. 2010 Aug 26;363(9):876-8
references.pmid: 20818849
references.citation: J Invest Dermatol. 2012 Mar;132(3 Pt 2):854-63
references.pmid: 22217739
references.citation: Cell Signal. 2008 Apr;20(4):684-94
references.pmid: 18249092
references.citation: Cancer Res. 2011 Apr 1;71(7):2750-60
references.pmid: 21317224
references.citation: Nat Rev Clin Oncol. 2010 Jul;7(7):367-80
references.pmid: 20551944
references.citation: Cancer Res. 2011 Jan 15;71(2):572-82
references.pmid: 21224358
references.citation: Expert Opin Investig Drugs. 2012 Apr;21(4):531-9
references.pmid: 22394161
references.citation: Lancet Oncol. 2012 Aug;13(8):782-9
references.pmid: 22805292
references.citation: Cancer Cell. 2010 Dec 14;18(6):683-95
references.pmid: 21156289
references.citation: Nat Commun. 2012 Mar 06;3:724
references.pmid: 22395615
references.citation: Cancer Cell. 2011 Jan 18;19(1):3-4
references.pmid: 21251608
references.citation: Nat Commun. 2013;4:1508
references.pmid: 23443536
references.citation: Cell. 1997 Feb 21;88(4):435-7
references.pmid: 9038334
references.citation: Oncogene. 2008 Oct 27;27(50):6473-88
references.pmid: 18955974
references.citation: Clin Cancer Res. 2011 Feb 15;17(4):721-30
references.pmid: 21088259
references.citation: J Transl Med. 2012 Mar 20;10:53
references.pmid: 22433222