Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests PP2A Reactivation as a Strategy to Treat c-KIT+ Cancers

Abstract

Oncogenic mutations of the receptor tyrosine kinase c-KIT play an important role in the pathogenesis of gastrointestinal stromal tumors, systemic mastocytosis, and some acute myeloid leukemias (AML). Although juxtamembrane mutations commonly detected in gastrointestinal stromal tumor are sensitive to tyrosine kinase inhibitors, the kinase domain mutations frequently encountered in systemic mastocytosis and AML confer resistance and are largely unresponsive to targeted inhibition by the existing agent imatinib. In this study, we show that myeloid cells expressing activated c-KIT mutants that are imatinib sensitive (V560G) or imatinib resistant (D816V) can inhibit the tumor suppressor activity of protein phosphatase 2A (PP2A). This effect was associated with the reduced expression of PP2A structural (A) and regulatory subunits (B55α, B56α, B56γ, and B56δ). Overexpression of PP2A-Aα in D816V c-KIT cells induced apoptosis and inhibited proliferation. In addition, pharmacologic activation of PP2A by FTY720 reduced proliferation, inhibited clonogenic potential, and induced apoptosis of mutant c-KIT + cells, while having no effect on wild-type c-KIT cells or empty vector controls. FTY720 treatment caused the dephosphorylation of the D816V c-KIT receptor and its downstream signaling targets pAkt, pSTAT5, and pERK1/2. Additionally, in vivo administration of FTY720 delayed the growth of V560G and D816V c-KIT tumors, inhibited splenic and bone marrow infiltration, and prolonged survival. Our findings show that PP2A inhibition is essential for c-KIT-mediated tumorigenesis, and that reactivating PP2A may offer an attractive strategy to treat drug-resistant c-KIT + cancers. Cancer Res; 70(13); 5438-47. ©2010 AACR.

Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma

“…18 Pharmacological activation of PP2A has been suggested as a promising strategy to treat c-KITC cancers. 19 Despite these anticancer effects, PP2A may play a tumor-promoting role in some settings. For instance, targeting PP2A via antisense technology results in decreased proliferation of human multiple myeloma cells.…”

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

“…It has been reported that impaired PP2A activity has a key role in BCR/ABL-positive leukemias, such as CML and acute lymphoblastic leukemia, 31,32 in myeloid precursors expressing imatinib-sensitive (V560G) and imatinib-resistant (D816 V) mutant c-KIT, 36 and also in chronic lymphocytic leukemia; 46 moreover, activation of PP2A by either FTY720 or forskolin seems to have promising therapeutic effects in these diseases. Abbreviation: AML, acute myeloid leukemia.…”

“…10 As indicated above, only few studies have reported reduced PP2A activity in AML. 35,36 Our group has recently reported an impaired PP2A activity by SET as a consequence of SETBP1 overexpression, a recurrent event in AML (27%). 37 This leads us to hypothesize that PP2A inhibition could be a recurrent event in AML.…”

“…Moreover, a recent study shows that activating c-KIT mutations inhibit PP2A, and that reactivation of PP2A effectively suppresses the in vitro and in vivo growth of imatinib-sensitive and imatinib-resistant c-KIT-positive cells, indicating that functional inactivation of PP2A tumor suppressor activity could represent a key step in the induction and maintenance of KIT-positive leukemias. 36 Our group has previously reported that SETBP1 overexpression is a recurrent event in AML, which impairs PP2A activity via SET and promotes proliferation of AML cells. 37 In addition, it has been reported that the activity of PP1 and PP2A is enhanced in the arsenic sulphide-induced differentiation of the AML cell line HL-60, 38 and that the alkylphosphocholine erucylphosphohomocholine is cytotoxic to AML cells through JNK-and PP2A-dependent mechanisms.…”

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

“…For example, FTY720 interacts with the cannabinoid family of GPCRs (77), but the primary cannabinoid receptors, CB 1 and CB 2 , are not involved in the EC barrier-enhancing response (70). In addition, FTY720 (but not S1P) inhibits S1PL (78), cytosolic phospholipase A 2 (79), and ceramide synthases (80,81), and activates protein phosphatase 2A (82). In human lung ECs, FTY720 increased c-Abelson tyrosine kinase (c-Abl) tyrosine kinase activity, and c-Abl siRNA attenuated FTY720-dependent barrier enhancement ( Figure 5) (83).…”