PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Pandolfi, Ashley; Stanley, Robert F.; Yu, Yiting; Bartholdy, Boris; Pendurti, Gopichand; Gritsman, Kira; Boultwood, Jacqueline; Chernoff, Jonathan; Verma, Amit; Steidl, Ulrich

doi:10.1182/blood-2014-12-618801

Cited by 55 publications

(63 citation statements)

References 32 publications

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“…The significances of expressions between low‐ and high‐risk groups are more pronounced with regard to levels of PAK2 than to PAK1 (the P ‐values differing 1·10 × 10 24 fold (BL), 3·25 × 10 66 fold (MM), and 9·25 × 10 16 fold (DLBCL); Fig 1A). In contrast, and in line with the proposed role of PAK1 in AML pathogenesis, levels of PAK1 are significantly upregulated in a high‐risk group of AML patients (Pandolfi et al , 2015), whereas levels of PAK2 are downregulated (Fig S1B).…”

Section: Resultssupporting

confidence: 76%

“…The level and the activity of PAK1 are increased in myelodysplastic syndrome (MDS) (Pandolfi et al , 2015), and a gain in PAK1 gene copy number was found in cutaneous T cell lymphoma (mycosis fungoides/Sezary syndrome) (Mao et al , 2003). The level of PAK2 is increased in mantle cell lymphoma (MCL) and in activated B‐cell like diffuse large B cell lymphoma (ABC‐like DLBCL) that harbour 3q29 amplifications.…”

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confidence: 99%

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Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

et al. 2017

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SummaryThe p21‐activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1 + haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2‐ but not shPAK1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.

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Section: Resultssupporting

confidence: 76%

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confidence: 99%

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

et al. 2017

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“…33 FRAX597, as an inhibitor of PAK1, has been tested on a number of cancers, such as skin cancer, squamous cell carcinomas, acute myeloid leukemia, non-small-cell lung cancer, and pancreatic cancer. 28,[33][34][35] FRAX597, as an inhibitor of PAK2, has also been shown to block enzyme-secretion by, and ERK1/2 activation of, pancreatic acinar cells (which only express PAK2) in response to gastrointestinal hormones and neurotransmitters. 36 FRAX597 as a group 1 PAK inhibitor has not been tested in PSCs in the context of pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of group 1 p21‐activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer

Yeo

Phillips

Baldwin

et al. 2017

Intl Journal of Cancer

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Pancreatic cancer remains one of the most lethal of all solid tumors. Pancreatic stellate cells (PSCs) are primarily responsible for the fibrosis that constitutes the stroma and p21-activated kinase 1 (PAK1) may have a role in signalling pathways involving PSCs. This study aimed to examine the role of PAK1 in PSCs and in the interaction of PSCs with pancreatic cancer cells. Human PSCs were isolated using the modified outgrowth method. The effect of inhibiting PAK1 with group 1 PAK inhibitor, FRAX597, on cell proliferation and apoptosis in vitro was measured by thymidine incorporation and annexin V assays, respectively. The effect of depleting host PAK1 on the survival of mice with pancreatic Pan02 cell tumors was evaluated using PAK1 knockout (KO) mice. PAK1 was expressed in isolated PSCs. FRAX597 reduced the activation of PSCs, inhibited PSC proliferation, and increased PSC apoptosis at least in partial by inhibiting PAK1 activity. The decreased expression and activity of PAK1 in PAK1 KO mice tumors was associated with an increased mouse survival. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis. Targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer.

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“…Given their role in tumor-related processes, PAK were proposed as possible targets in anticancer treatment (34)(35)(36)(37)(38). However, with regard to specific functions of different family members, it will be necessary to search for more specific PAK inhibitors or to inhibit specific downstream effectors.…”

Section: Introductionmentioning

confidence: 99%

PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions

Grebeňová

Holoubek

RoÌˆselova

et al. 2019

Preprint

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P21-activated kinases (PAK) are key effectors of the small GTPases Rac1 and Cdc42, as well as of Src family kinases. In particular, PAK1 has several well-documented roles, both kinase-dependent and kinase-independent, in cancer-related processes, such as cell proliferation, adhesion, and migration. However, PAK1 properties and functions have not been attributed to individual PAK1 isoforms: besides the full-length kinase (PAK1-full), a splicing variant lacking the exon 15 (PAK1∆15) is annotated in protein databases. In addition, it is not clear if PAK1 and PAK2 are functionally overlapping. Using fluorescently tagged forms of human PAK1-full, PAK1∆15, and PAK2, we analyzed their intracellular localization and mutual interactions. Effects of PAK inhibition or depletion on cell-surface adhesion were monitored by real-time microimpedance measurement. We show that PAK1∆15 is in many aspects similar to PAK2, rather than to PAK1-full. Both PAK1∆15 and PAK2, but not PAK1-full, were enriched in focal adhesions, indicating that the C-terminus might be important for PAK intracellular localization. Using immunoprecipitation, we documented direct interactions among the studied PAK group I members: PAK1 and PAK2 form homodimers, but all possible heterodimers were also detected. Our results indicate that PAK1 and PAK2 have distinct roles in cell adhesion and mutually affect their function. PAK1full is required for formation of membrane protrusions, whereas PAK2 is involved in focal adhesion assembly. We have also noted that PAK inhibition was associated with a large reduction of the cell glycolytic rate. Altogether, our data suggest a complex interplay among different PAK group I members, which have largely non-redundant functions.PAK (p21-activated kinases) are a group of serine-threonine kinases originally identified as downstream effectors of p21 proteins, specifically of the Ras-related GTPases Rac1 and Cdc42 (1, 2). The initial phase of PAK research focused on their role as small GTPase effectors in the context of dynamic remodelling of the cytoskeleton and of cell adhesion structures (3). Later on, PAK were found to be involved in many cancer-related processes in different tumor types (4, 5). In parallel, the discovery of PAK1 nuclear localization (6) prompted the analysis of PAK functions in the cell nucleus.The human PAK family is divided into the group I (PAK1 to PAK3) and group II (PAK4 to PAK6). In general, these kinases regulate the cytoskeleton dynamics, intracellular signaling, and gene expression (7). The current knowledge about PAK group I is derived mostly from adherent cell models, where PAK activity usually correlates with increased cell motility. In this area, the research was mainly focused to PAK1, although some important differences between PAK1 and PAK2 have been reported (8). In addition, PAK are known regulators of a wide range of cellular processes, including the dynamics of actin structures and microtubules, cell division, apoptosis, and adhesion to the extracellular matrix.Despite considerable seque...

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PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Abstract: Key Points Targeting of PAK1 inhibits primary AML and MDS patients' cells including leukemia stem cells but spares healthy stem and progenitor cells. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC and a core network of MYC target genes.

Cited by 55 publications

References 32 publications

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

Inhibition of group 1 p21‐activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer

PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions

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PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Abstract: Key Points Targeting of PAK1 inhibits primary AML and MDS patients' cells including leukemia stem cells but spares healthy stem and progenitor cells. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC and a core network of MYC target genes.

Cited by 55 publications

References 32 publications

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

Inhibition of group 1 p21‐activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer

PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions

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Product

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Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1