Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

p21-Activated kinases as promising therapeutic targets in hematological malignancies

Abstract

The p21-Activated Kinases (PAKs) are a family of six serine/threonine kinases that were originally identified as downstream effectors of the Rho GTPases Cdc42 and Rac. Since the first PAK was discovered in 1994, studies have revealed their fundamental and biological importance in the development of physiological systems. Within the cell, PAKs also play significant roles in regulating essential cellular processes such as cytoskeletal dynamics, gene expression, cell survival, and cell cycle progression. These processes are often deregulated in numerous cancers when different PAKs are overexpressed or amplified at the chromosomal level. Furthermore, PAKs modulate multiple oncogenic signaling pathways which facilitate apoptosis escape, uncontrolled proliferation, and drug resistance. There is growing insight into the critical roles of PAKs in regulating steady-state hematopoiesis, including the properties of hematopoietic stem cells (HSC), and the initiation and progression of hematological malignancies. This review will focus on the most recent studies that provide experimental evidence showing how specific PAKs regulate the properties of leukemic stem cells (LSCs) and drug-resistant cells to initiate and maintain hematological malignancies. The current understanding of the molecular and cellular mechanisms by which the PAKs operate in specific human leukemia or lymphomas will be discussed. From a translational point of view, PAKs have been suggested to be critical therapeutic targets and potential prognosis markers; thus, this review will also discuss current therapeutic strategies against hematological malignancies using existing small-molecule PAK inhibitors, as well as promising combination treatments, to sensitize drug-resistant cells to conventional therapies. The challenges of toxicity and non-specific targeting associated with some PAK inhibitors, as well as how future approaches for PAK inhibition to overcome these limitations, will also be addressed.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Group I and Group II p21-Activated Kinase Structure and Mechanisms of Activation.
Fig. 2: Role of PAK Kinases in Hematological Malignancies.
Fig. 3: Structures of PAK Small Molecule Inhibitors Commonly Used Against Hematological Malignancies.

References

  1. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994;367:40–6. Jan 6PubMed PMID: 8107774. Epub 1994/01/06.

    CAS  PubMed  Google Scholar 

  2. Bagrodia S, Cerione RA. Pak to the future. Trends Cell Biol. 1999;9:350–5. SepPubMed PMID: 10461188. Epub 1999/08/26.

    CAS  PubMed  Google Scholar 

  3. Rane CK, Minden A. P21 activated kinases: structure, regulation, and functions. Small GTPases. 2014;5. PubMed PMID: 24658305. Pubmed Central PMCID: PMC4160339. Epub 2014/03/25.

  4. Chong C, Tan L, Lim L, Manser E. The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity. J Biol Chem. 2001;276:17347–53. May 18PubMed PMID: 11278486. Epub 2001/03/30.

    CAS  PubMed  Google Scholar 

  5. Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol. 2002;34:713–7. JulPubMed PMID: 11950587. Epub 2002/04/16.

    CAS  PubMed  Google Scholar 

  6. Baskaran Y, Ng YW, Selamat W, Ling FT, Manser E. Group I and II mammalian PAKs have different modes of activation by Cdc42. EMBO Rep. 2012;13:653–9. Jun 29PubMed PMID: 22653441. Pubmed Central PMCID: PMC3388789. Epub 2012/06/02.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, et al. Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate. Proc Natl Acad Sci USA. 2012;109:16107–12. Oct 2PubMed PMID: 22988085. Pubmed Central PMCID: PMC3479536. Epub 2012/09/19.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kelly ML, Chernoff J. Mouse models of PAK function. Cell Logist. 2012;2:84–8. Apr 1PubMed PMID: 23162740. Pubmed Central PMCID: PMC3490966. Epub 2012/11/20.

    PubMed  PubMed Central  Google Scholar 

  9. Zeng Y, Broxmeyer HE, Staser K, Chitteti BR, Park SJ, Hahn S, et al. Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation. Stem Cells. 2015;33:1630–41. MayPubMed PMID: 25586960. Pubmed Central PMCID: PMC4409559. Epub 2015/01/15.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Radu M, Lyle K, Hoeflich KP, Villamar-Cruz O, Koeppen H, Chernoff J. p21-Activated kinase 2 regulates endothelial development and function through the Bmk1/Erk5 pathway. Mol Cell Biol. 2015;35:3990–4005. DecPubMed PMID: 26391956. Pubmed Central PMCID: PMC4628059. Epub 2015/09/24.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Won SY, Park JJ, Shin EY, Kim EG. PAK4 signaling in health and disease: defining the PAK4-CREB axis. Exp Mol Med. 2019;51:1–9. Feb 12PubMed PMID: 30755582. Pubmed Central PMCID: PMC6372590. Epub 2019/02/14.

    CAS  PubMed  Google Scholar 

  12. Tian Y, Lei L, Minden A. A key role for Pak4 in proliferation and differentiation of neural progenitor cells. Dev Biol. 2011;353:206–16. May 15PubMed PMID: 21382368. Epub 2011/03/09.

    CAS  PubMed  Google Scholar 

  13. Nekrasova T, Minden A. Role for p21-activated kinase PAK4 in development of the mammalian heart. Transgenic Res. 2012;21:797–811. AugPubMed PMID: 22173944. Epub 2011/12/17.

    CAS  PubMed  Google Scholar 

  14. Vadlamudi RK, Li F, Adam L, Nguyen D, Ohta Y, Stossel TP, et al. Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. Nat Cell Biol. 2002;4:681–90. SepPubMed PMID: 12198493. Epub 2002/08/29.

    CAS  PubMed  Google Scholar 

  15. Meng J, Meng Y, Hanna A, Janus C, Jia Z. Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. J Neurosci. 2005;25:6641–50. Jul 13PubMed PMID: 16014725. Pubmed Central PMCID: PMC6725420. Epub 2005/07/15.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Pandey A, Dan I, Kristiansen TZ, Watanabe NM, Voldby J, Kajikawa E, et al. Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain. Oncogene 2002;21:3939–48. May 30PubMed PMID: 12032833. Epub 2002/05/29.

    CAS  PubMed  Google Scholar 

  17. Dan C, Nath N, Liberto M, Minden APAK5. a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells. Mol Cell Biol. 2002;22:567–77. JanPubMed PMID: 11756552. Pubmed Central PMCID: PMC139731. Epub 2002/01/05.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM. Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling. J Biol Chem. 2004;279:1922–31. Jan 16PubMed PMID: 14573606. Epub 2003/10/24.

    CAS  PubMed  Google Scholar 

  19. Kumar R, Li DQ. PAKs in human cancer progression: from inception to cancer therapeutic to future oncobiology. Adv Cancer Res. 2016;130:137–209. PubMed PMID: 27037753. Epub 2016/04/03

    CAS  PubMed  Google Scholar 

  20. Arias-Romero LE, Villamar-Cruz O, Huang M, Hoeflich KP, Chernoff J. Pak1 kinase links ErbB2 to beta-catenin in transformation of breast epithelial cells. Cancer Res. 2013;73:3671-82. PubMed PMID: 23576562. Pubmed Central PMCID: PMC3687032. Epub 2013/04/12.

  21. Jagadeeshan S, Subramanian A, Tentu S, Beesetti S, Singhal M, Raghavan S, et al. P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer. Ann Oncol. 2016;27:1546–56. AugPubMed PMID: 27117533. Epub 2016/04/28.

    CAS  PubMed  Google Scholar 

  22. Tyagi N, Bhardwaj A, Singh AP, McClellan S, Carter JE, Singh S. p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-kappaB pathway. Oncotarget. 2014;5:8778–89. Sep 30PubMed PMID: 25238288. Pubmed Central PMCID: PMC4226721. Epub 2014/09/23.

    PubMed  PubMed Central  Google Scholar 

  23. Tyagi N, Marimuthu S, Bhardwaj A, Deshmukh SK, Srivastava SK, Singh AP, et al. p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling. Cancer Lett. 2016;370:260–7. Jan 28PubMed PMID: 26546043. Pubmed Central PMCID: PMC4684758. Epub 2015/11/08.

    CAS  PubMed  Google Scholar 

  24. He LF, Xu HW, Chen M, Xian ZR, Wen XF, Chen MN, et al. Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling. Oncotarget. 2017;8:17573–85. Mar 14PubMed PMID: 28407679. Pubmed Central PMCID: PMC5392270. Epub 2017/04/15.

    PubMed  Google Scholar 

  25. Zhuang T, Zhu J, Li Z, Lorent J, Zhao C, Dahlman-Wright K, et al. p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells. Oncotarget. 2015;6:43853–68. Dec 22PubMed PMID: 26554417. Pubmed Central PMCID: PMC4791272. Epub 2015/11/12.

    PubMed  PubMed Central  Google Scholar 

  26. Rane C, Senapedis W, Baloglu E, Landesman Y, Crochiere M, Das-Gupta S, et al. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth. Sci Rep. 2017;7:42555. Feb 15PubMed PMID: 28198380. Pubmed Central PMCID: PMC5309789. Epub 2017/02/16.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Li SQ, Wang ZH, Mi XG, Liu L, Tan Y. MiR-199a/b-3p suppresses migration and invasion of breast cancer cells by downregulating PAK4/MEK/ERK signaling pathway. IUBMB Life. 2015;67:768–77. OctPubMed PMID: 26399456. Epub 2015/09/25.

    CAS  PubMed  Google Scholar 

  28. Chen J, Lu H, Yan D, Cui F, Wang X, Yu F, et al. PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy. Oncotarget. 2015;6:355–67. Jan 1PubMed PMID: 25426562. Pubmed Central PMCID: PMC4381600. Epub 2014/11/27.

    PubMed  Google Scholar 

  29. Rane CK, Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019;54:40–9. PubMed PMID: 29330094. Epub 2018/01/14.

  30. Wang Z, Fu M, Wang L, Liu J, Li Y, Brakebusch C, et al. p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner. J Biol Chem. 2013;288:20093–9. Jul 5PubMed PMID: 23653349. Pubmed Central PMCID: PMC3707706. Epub 2013/05/09.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Thillai K, Lam H, Sarker D, Wells CM. Deciphering the link between PI3K and PAK: an opportunity to target key pathways in pancreatic cancer? Oncotarget. 2017;8:14173–91. Feb 21PubMed PMID: 27845911. Pubmed Central PMCID: PMC5355171. Epub 2016/11/16.

    PubMed  Google Scholar 

  32. Li Y, Shao Y, Tong Y, Shen T, Zhang J, Li Y, et al. Nucleo-cytoplasmic shuttling of PAK4 modulates beta-catenin intracellular translocation and signaling. Biochim Biophys Acta. 2012;1823:465–75. FebPubMed PMID: 22173096. Epub 2011/12/17.

    CAS  PubMed  Google Scholar 

  33. Wong LE, Reynolds AB, Dissanayaka NT, Minden A. p120-catenin is a binding partner and substrate for Group B Pak kinases. J Cell Biochem. 2010;110:1244–54. Aug 1PubMed PMID: 20564219. Epub 2010/06/22.

    CAS  PubMed  Google Scholar 

  34. Jin S, Zhuo Y, Guo W, Field J. p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. J Biol Chem. 2005;280:24698–705. Jul 1PubMed PMID: 15849194. Epub 2005/04/26.

    CAS  PubMed  Google Scholar 

  35. Wu X, Carr HS, Dan I, Ruvolo PP, Frost JA. p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. J Cell Biochem. 2008;105:167–75. PubMed PMID: 18465753. Pubmed Central PMCID: PMC2575069. Epub 2008/05/10.

  36. Gnesutta N, Minden A. Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol Cell Biol. 2003;23:7838–48. NovPubMed PMID: 14560027. Pubmed Central PMCID: PMC207651. Epub 2003/10/16.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Reddy SD, Ohshiro K, Rayala SK, Kumar R. MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer Res. 2008;68:8195–200. Oct 15PubMed PMID: 18922890. Pubmed Central PMCID: PMC3636563. Epub 2008/10/17.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Xue J, Chen LZ, Li ZZ, Hu YY, Yan SP, Liu LY. MicroRNA-433 inhibits cell proliferation in hepatocellular carcinoma by targeting p21 activated kinase (PAK4). Mol Cell Biochem. 2015;399:77–86. JanPubMed PMID: 25410752. Epub 2014/11/21.

    CAS  PubMed  Google Scholar 

  39. Li Q, Wu X, Guo L, Shi J, Li J. MicroRNA-7-5p induces cell growth inhibition, cell cycle arrest and apoptosis by targeting PAK2 in non-small cell lung cancer. FEBS Open Bio. 2019;9:1983–93. NovPubMed PMID: 31587474. Pubmed Central PMCID: PMC6823280. Epub 2019/10/07.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhan L, Pan Y, Chen L, Chen Z, Zhang H, Sun C. MicroRNA-526a targets p21-activated kinase 7 to inhibit tumorigenesis in hepatocellular carcinoma. Mol Med Rep. 2017 Jul;16:837-44. PubMed PMID: 28560394. Epub 2017/06/01.

  41. Song X, Xie Y, Liu Y, Shao M, Yang W. MicroRNA-492 overexpression exerts suppressive effects on the progression of osteosarcoma by targeting PAK7. Int J Mol Med. 2017;40:891–7. SepPubMed PMID: 28677719. Epub 2017/07/06.

    CAS  PubMed  Google Scholar 

  42. Lin H, Rothe K, Chen M, Wu A, Babaian A, Yen R, et al. The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML. Blood. 2020;136:596–609. Jul 30PubMed PMID: 32270193. Pubmed Central PMCID: PMC7485576. Epub 2020/04/10.

    PubMed  PubMed Central  Google Scholar 

  43. Seita J, Weissman IL. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med. 2010;2:640–53. Nov-DecPubMed PMID: 20890962. Pubmed Central PMCID: PMC2950323. Epub 2010/10/05.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Eaves CJ. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood. 2015;125:2605–13. Apr 23PubMed PMID: 25762175. Pubmed Central PMCID: PMC4440889. Epub 2015/03/13.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Man Y, Yao X, Yang T, Wang Y. Hematopoietic stem cell niche during homeostasis, malignancy, and bone marrow transplantation. Front Cell Dev Biol. 2021;9:621214. PubMed PMID: 33553181. Pubmed Central PMCID: PMC7862549. Epub 2021/02/09

    PubMed  PubMed Central  Google Scholar 

  46. Sweeney C, Vyas P. The graft-versus-leukemia effect in AML. Front Oncol. 2019;9:1217. PubMed PMID: 31803612. Pubmed Central PMCID: PMC6877747. Epub 2019/12/06

    PubMed  PubMed Central  Google Scholar 

  47. Reddy PN, Radu M, Xu K, Wood J, Harris CE, Chernoff J, et al. p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with beta-Pix. Blood. 2016;127:1967–75. Apr 21PubMed PMID: 26932803. Pubmed Central PMCID: PMC4841040. Epub 2016/03/05.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Dorrance AM, De Vita S, Radu M, Reddy PN, McGuinness MK, Harris CE, et al. The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment. Blood. 2013;121:2474–82. Mar 28PubMed PMID: 23335370. Pubmed Central PMCID: PMC3612857. Epub 2013/01/22.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kirtonia A, Pandya G, Sethi G, Pandey AK, Das BC, Garg M. A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia. J Mol Med. 2020;98:1069-91. PubMed PMID: 32620999. Epub 2020/07/06.

  50. Hanekamp D, Cloos J, Schuurhuis GJ. Leukemic stem cells: identification and clinical application. Int J Hematol. 2017;105:549–57. MayPubMed PMID: 28357569. Epub 2017/03/31.

    CAS  PubMed  Google Scholar 

  51. van Gils N, Denkers F, Smit L. Escape from treatment; the different faces of leukemic stem cells and therapy resistance in acute myeloid leukemia. Front Oncol. 2021;11:659253. PubMed PMID: 34012921. Pubmed Central PMCID: PMC8126717. Epub 2021/05/21

    PubMed  PubMed Central  Google Scholar 

  52. Pandolfi A, Stanley RF, Yu Y, Bartholdy B, Pendurti G, Gritsman K, et al. PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2015;126:1118–27. Aug 27PubMed PMID: 26170031. Pubmed Central PMCID: PMC4551362. Epub 2015/07/15.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chatterjee A, Ghosh J, Ramdas B, Mali RS, Martin H, Kobayashi M, et al. Regulation of Stat5 by FAK and PAK1 in oncogenic FLT3- and KIT-driven leukemogenesis. Cell Rep. 2014;9:1333–48. Nov 20PubMed PMID: 25456130. Pubmed Central PMCID: PMC4380442. Epub 2014/12/03.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Shankar DB, Cheng JC, Kinjo K, Federman N, Moore TB, Gill A, et al. The role of CREB as a proto-oncogene in hematopoiesis and in acute myeloid leukemia. Cancer Cell. 2005;7:351–62. AprPubMed PMID: 15837624. Epub 2005/04/20.

    CAS  PubMed  Google Scholar 

  55. Kaufmann KB, Garcia-Prat L, Liu Q, Ng SWK, Takayanagi SI, Mitchell A, et al. A stemness screen reveals C3orf54/INKA1 as a promoter of human leukemia stem cell latency. Blood. 2019;133:2198–211. May 16PubMed PMID: 30796022. Epub 2019/02/24.

    CAS  PubMed  Google Scholar 

  56. Quan L, Cheng Z, Dai Y, Jiao Y, Shi J, Fu L. Prognostic significance of PAK family kinases in acute myeloid leukemia. Cancer Gene Ther. 2020;27:30–7. FebPubMed PMID: 30890765. Epub 2019/03/21.

    CAS  PubMed  Google Scholar 

  57. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343–56. Nov 15PubMed PMID: 11071626. Epub 2000/11/09.

    CAS  PubMed  Google Scholar 

  58. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319-25. PubMed PMID: 11756187. Epub 2002/01/05.

  59. Houshmand M, Simonetti G, Circosta P, Gaidano V, Cignetti A, Martinelli G, et al. Chronic myeloid leukemia stem cells. Leukemia. 2019;33:1543–56. JulPubMed PMID: 31127148. Pubmed Central PMCID: PMC6755964. Epub 2019/05/28.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94:2056–64. Sep 15PubMed PMID: 10477735

    CAS  PubMed  Google Scholar 

  61. Bolton-Gillespie E, Schemionek M, Klein HU, Flis S, Hoser G, Lange T, et al. Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells. Blood. 2013;121:4175–83. May 16PubMed PMID: 23543457. Pubmed Central PMCID: PMC3656452. Epub 2013/04/02.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Edlinger L, Berger-Becvar A, Menzl I, Hoermann G, Greiner G, Grundschober E, et al. Expansion of BCR/ABL1(+) cells requires PAK2 but not PAK1. Br J Haematol. 2017;179:229–41. OctPubMed PMID: 28707321. Pubmed Central PMCID: PMC5655792. Epub 2017/07/15.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Berger A, Hoelbl-Kovacic A, Bourgeais J, Hoefling L, Warsch W, Grundschober E, et al. PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis. Leukemia. 2014;28:629–41. MarPubMed PMID: 24263804. Pubmed Central PMCID: PMC3948164. Epub 2013/11/23.

    CAS  PubMed  Google Scholar 

  64. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758–64. Apr 12PubMed PMID: 17344859. Epub 2007/03/09.

    CAS  PubMed  Google Scholar 

  65. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106:3760–7. Dec 1PubMed PMID: 16105981. Epub 2005/08/18.

    CAS  PubMed  Google Scholar 

  66. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18:547–61. FebPubMed PMID: 10653870. Epub 2000/02/02.

    CAS  PubMed  Google Scholar 

  67. Ravandi F, O’Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, et al. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121:4158–64. Dec 1PubMed PMID: 26308885. Pubmed Central PMCID: PMC4666803. Epub 2015/08/27.

    CAS  PubMed  Google Scholar 

  68. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7:e577. Jun 30 PubMed PMID: 28665419. Pubmed Central PMCID: PMC5520400. Epub 2017/07/01

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Siekmann IK, Dierck K, Prall S, Klokow M, Strauss J, Buhs S, et al. Combined inhibition of receptor tyrosine and p21-activated kinases as a therapeutic strategy in childhood ALL. Blood Adv. 2018;2:2554–67. Oct 9PubMed PMID: 30301811. Pubmed Central PMCID: PMC6177654. Epub 2018/10/12.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Takao S, Chien W, Madan V, Lin DC, Ding LW, Sun QY, et al. Targeting the vulnerability to NAD(+) depletion in B-cell acute lymphoblastic leukemia. Leukemia. 2018;32:616–25. MarPubMed PMID: 28904384. Epub 2017/09/15.

    CAS  PubMed  Google Scholar 

  71. Bellan C, Stefano L, Giulia de F, Rogena EA, Lorenzo L. Burkitt lymphoma versus diffuse large B-cell lymphoma: a practical approach. Hematol Oncol. 2010;28:53–6. JunPubMed PMID: 19844983. Epub 2009/10/22.

    PubMed  Google Scholar 

  72. Bagherani N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Res. 2016;5. PubMed PMID: 27540476. Pubmed Central PMCID: PMC4965697. Epub 2016/08/20.

  73. Wang Y, Gu X, Li W, Zhang Q, Zhang C. PAK1 overexpression promotes cell proliferation in cutaneous T cell lymphoma via suppression of PUMA and p21. J Dermatol Sci. 2018;90:60–7. AprPubMed PMID: 29307600. Epub 2018/01/09.

    CAS  PubMed  Google Scholar 

  74. Watanabe T. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood. 2017;129:1071–81. Mar 2PubMed PMID: 28115366. Pubmed Central PMCID: PMC5374731. Epub 2017/01/25.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ramos JC. Choices and challenges in the treatment of adult T-cell leukemia/lymphoma. J Oncol Pract.2017;138:495–7. AugPubMed PMID: 28796965. Epub 2017/08/11.

    Google Scholar 

  76. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47:1304–15. NovPubMed PMID: 26437031. Epub 2015/10/06.

    CAS  PubMed  Google Scholar 

  77. Chung EY, Mai Y, Shah UA, Wei Y, Ishida E, Kataoka K, et al. PAK kinase inhibition has therapeutic activity in novel preclinical models of adult T-cell leukemia/lymphoma. Clin Cancer Res. 2019;25:3589–601. Jun 15PubMed PMID: 30862694. Epub 2019/03/14.

    CAS  PubMed  Google Scholar 

  78. Debes-Marun CS, Dewald GW, Bryant S, Picken E, Santana-Davila R, Gonzalez-Paz N, et al. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia. 2003;17:427–36. FebPubMed PMID: 12592343. Epub 2003/02/20.

    CAS  PubMed  Google Scholar 

  79. Hurt EM, Wiestner A, Rosenwald A, Shaffer AL, Campo E, Grogan T, et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell. 2004;5:191–9. FebPubMed PMID: 14998494. Epub 2004/03/05.

    CAS  PubMed  Google Scholar 

  80. Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M, et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood. 2004;103:3521–8. May 1PubMed PMID: 14715624. Epub 2004/01/13.

    CAS  PubMed  Google Scholar 

  81. Pinto V, Bergantim R, Caires HR, Seca H, Guimaraes JE, Vasconcelos MH. Multiple myeloma: available therapies and causes of drug resistance. Cancers. 2020;12. PubMed PMID: 32050631. Pubmed Central PMCID: PMC7072128. Epub 2020/02/14.

  82. Rousseau S, Dolado I, Beardmore V, Shpiro N, Marquez R, Nebreda AR, et al. CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway. Cell Signal. 2006;18:1897–905. NovPubMed PMID: 16574378. Epub 2006/04/01.

    CAS  PubMed  Google Scholar 

  83. Ro TB, Holien T, Fagerli UM, Hov H, Misund K, Waage A, et al. HGF and IGF-1 synergize with SDF-1alpha in promoting migration of myeloma cells by cooperative activation of p21-activated kinase. Exp Hematol. 2013;41:646–55. JulPubMed PMID: 23499762. Epub 2013/03/19.

    PubMed  Google Scholar 

  84. Holt RU, Fagerli UM, Baykov V, Ro TB, Hov H, Waage A, et al. Hepatocyte growth factor promotes migration of human myeloma cells. Haematologica. 2008;93:619-22. PubMed PMID: 18326526. Epub 2008/03/11.

  85. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood. 2007;109:2708–17. Apr 1PubMed PMID: 17119115. Pubmed Central PMCID: PMC1852222. Epub 2006/11/23.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Fulciniti M, Martinez-Lopez J, Senapedis W, Oliva S, Lakshmi Bandi R, Amodio N, et al. Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma. Blood. 2017;129:2233–45. Apr 20PubMed PMID: 28096095. Pubmed Central PMCID: PMC5399480. Epub 2017/01/18.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Babagana M, Johnson S, Slabodkin H, Bshara W, Morrison C, Kandel ES. P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells. Mol Carcinog. 2017;56:1515–25. MayPubMed PMID: 28052407. Pubmed Central PMCID: PMC5392142. Epub 2017/01/05.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Walsh K, McKinney MS, Love C, Liu Q, Fan A, Patel A, et al. PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin Cancer Res. 2013;19:1106–15. Mar 1PubMed PMID: 23300274. Pubmed Central PMCID: PMC3594365. Epub 2013/01/10.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Flis S, Bratek E, Chojnacki T, Piskorek M, Skorski T. Simultaneous Inhibition of BCR-ABL1 tyrosine kinase and PAK1/2 serine/threonine kinase exerts synergistic effect against chronic myeloid leukemia cells. Cancers. 2019;11. PubMed PMID: 31614827. Pubmed Central PMCID: PMC6826736. Epub 2019/10/17.

  90. Rudolph J, Crawford JJ, Hoeflich KP, Wang W. Inhibitors of p21-activated kinases (PAKs). J Med Chem. 2015;58:111–29. Jan 8PubMed PMID: 25415869. Epub 2014/11/22.

    CAS  PubMed  Google Scholar 

  91. Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci USA. 2010;107:9446-51. PubMed PMID: 20439741. Pubmed Central PMCID: PMC2889050. Epub 2010/05/05.

  92. Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, et al. Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor. Cancer Lett. 2014;349:45–50. Jul 10PubMed PMID: 24704155. Epub 2014/04/08.

    CAS  PubMed  Google Scholar 

  93. Kim DJ, Choi CK, Lee CS, Park MH, Tian X, Kim ND, et al. Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain. Exp Mol Med. 2016;48:e229. Apr 29PubMed PMID: 27126178. Pubmed Central PMCID: PMC4855275. Epub 2016/04/30

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, et al. Novel p21-activated kinase 4 (PAK4) allosteric modulators overcome drug resistance and stemness in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2017;16:76-87. PubMed PMID: 28062705. Pubmed Central PMCID: PMC5221563. Epub 2017/01/08.

  95. Mitchell SR, Larkin K, Grieselhuber NR, Lai TH, Cannon M, Orwick S, et al. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia. Blood Adv. 2019;3:242–55. Feb 12PubMed PMID: 30692102. Pubmed Central PMCID: PMC6373756. Epub 2019/01/30.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kuzelova K, Grebenova D, Holoubek A, Roselova P, Obr A, Group I. PAK inhibitor IPA-3 induces cell death and affects cell adhesivity to fibronectin in human hematopoietic cells. PLoS One. 2014;9:e92560. PubMed PMID: 24664099. Pubmed Central PMCID: PMC3963893. Epub 2014/03/26

    PubMed  PubMed Central  Google Scholar 

  97. Kuzelova K, Obr A, Roselova P, Grebenova D, Otevrelova P, Brodska B, et al. Group I p21-activated kinases in leukemia cell adhesion to fibronectin. Cell Adh Migr. 2021;15:18–36. PubMed PMID: 33464167. Pubmed Central PMCID: PMC7834095. Epub 2021/01/20.

  98. Huynh N, Wang K, Yim M, Dumesny CJ, Sandrin MS, Baldwin GS, et al. Depletion of p21-activated kinase 1 up-regulates the immune system of APC(14/+) mice and inhibits intestinal tumorigenesis. BMC Cancer. 2017;17:431. Jun 19PubMed PMID: 28629331. Pubmed Central PMCID: PMC5477105. Epub 2017/06/21.

    PubMed  PubMed Central  Google Scholar 

  99. Wang K, Huynh N, Wang X, Baldwin G, Nikfarjam M, He H. Inhibition of p21 activated kinase enhances tumour immune response and sensitizes pancreatic cancer to gemcitabine. Int J Oncol. 2018;52:261–9. JanPubMed PMID: 29115428. Epub 2017/11/09.

    CAS  PubMed  Google Scholar 

  100. Nasmall yi UA, Merhi M, Inchakalody V, Fernandes Q, Mestiri S, Prabhu KS, et al. The role of PAK4 in the immune system and its potential implication in cancer immunotherapy. Cell Immunol. 2021;367:104408. Jul 1PubMed PMID: 34246086. Epub 2021/07/11.

    Google Scholar 

Download references

Acknowledgements

XJ is generously supported by the Canadian Institutes of Health Research (CIHR), the Canadian Cancer Society, and the Leukemia & Lymphoma Society of Canada. AW received a MITACS Accelerate Fellowship. We also acknowledge many colleagues whose relevant research we were not able to cite due to space limitations.

Author information

Authors and Affiliations

Authors

Contributions

AW reviewed the literature and wrote the manuscript and XJ edited the manuscript.

Corresponding author

Correspondence to Xiaoyan Jiang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, A., Jiang, X. p21-Activated kinases as promising therapeutic targets in hematological malignancies. Leukemia 36, 315–326 (2022). https://doi.org/10.1038/s41375-021-01451-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01451-7

Search

Quick links