The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner

Sun, Jianmin; Mohlin, Sofie; Lundby, Alicia; Hellman, Ulf; Påhlman, Sven; Olsen, Jesper V.; Kazi, Julhash U.

doi:10.1038/onc.2013.479

Cited by 16 publications

(30 citation statements)

References 40 publications

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“…3, 21, 22 Recently, we have shown that, in addition to mutations in these genes, activation of other downstream kinases, such as SYK and p110, contribute to hematopoietic malignancies by activating the PI3K/mTOR pathway. 23, 24 Several PI3K/mTOR inhibitors have been used in the treatment of solid tumors and hematological malignancies. The majority of these inhibitors target mTOR, whereas others target AKT and PI3K.…”

Section: Introductionmentioning

confidence: 99%

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

et al. 2016

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Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.

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Section: Introductionmentioning

confidence: 99%

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

et al. 2016

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“…KIT is overexpressed or mutated in many cancers including small cell lung carcinoma (SCLC), malignant melanoma, colorectal cancer, mastocytosis, acute myeloid leukemia, testicular germ cell tumors, gastrointestinal stromal tumors (GISTs). Oncogenic KIT has the ability of the activating survival signaling constitutively independent of ligand expression [49][50][51][52]. SOCS6 interacts with KIT in response to the KIT-ligand stem cell factor (SCF) stimulation suggesting that the interaction is tyrosine phosphorylation dependent [5].…”

Section: Socs6 Is a Negative Regulator Of Kit Signalingmentioning

confidence: 99%

SOCS6 is a selective suppressor of receptor tyrosine kinase signaling

2014

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General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal AbstractThe suppressors of cytokine signaling (SOCS) are well known negative regulators of cytokine receptor signaling. SOCS6 is one of eight members of the SOCS family of proteins. Similar to other SOCS proteins, SOCS6 consists of an uncharacterized extended N-terminal region followed by an SH2 domain and a SOCS box. Unlike other SOCS proteins, SOCS6 is mainly involved in negative regulation of receptor tyrosine kinase signaling. SOCS6 is widely expressed in many tissues and is found to be downregulated in many cancers including colorectal cancer, gastric cancer, lung cancer, ovarian cancer, stomach cancer, thyroid cancer, hepatocellular carcinoma and pancreatic cancer. SOCS6 is involved in negative regulation of receptor signaling by increasing degradation mediated by ubiquitination of receptors or substrate proteins and induces apoptosis by targeting mitochondrial proteins. Therefore, SOCS6 turns out as an important regulator of survival signaling and its activity is required for controlling receptor tyrosine kinase signaling.

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“…Ligand-independent activation of c-Kit/V560D is dependent on PI3 kinase in a lipid kinase independent manner PI3 kinase plays an important role in the ligand-independent signaling by c-Kit/D816V, and cKit/D816V-mediated cell transformation is independent of its lipid kinase activity [5]. PI3 kinase binds to pY721 in c-Kit [18] and the binding requires the motif pYXXM in c-Kit [19].…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the most commonly identified c-Kit mutant, D816V, has been shown to be dependent on PI3 kinase for its transforming ability [18], thus making PI3-kinase an attractive target in the treatment of malignancies carrying the c-Kit/D816V mutant. In addition to its lipid kinase activity, we have recently demonstrated that the important role of PI3-kinase in c-Kit/D816V mediated cell transformation is independent on its lipid kinase activity [5]. Since currently available PI3-kinase inhibitors block the lipid kinase activity and no other functions of PI3-kinase, such as binding to other signal transduction molecules, they are probably of low clinical efficacy in this type of malignancies.…”

Section: Discussionmentioning

confidence: 99%

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PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner

Lindblad

Kazi

Sun

2015

Cell. Mol. Life Sci.

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Oncogenic mutants of c-Kit are often found in mastocytosis, gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML). The activation mechanism of the most commonly occurring mutation, D816V in exon 17 of c-Kit, has been well-studied while other mutations remain fairly uncharacterized in this respect. In this study, we show that the constitutive activity of the exon 11 mutant V560D is weaker than the D816V mutant. Phosphorylation of downstream signaling proteins induced by the ligand for c-Kit, stem cell factor (SCF), was stronger in cKit/V560D expressing cells than in cells expressing c-kit/D816V. Although cells expressing cKit/V560D showed increased ligand-independent proliferation and survival compared to wildtype c-Kit expressing cells, these biological effects were weaker than in c-Kit/D816V expressing cells. In contrast to cells expressing wild-type c-Kit, cells expressing c-Kit/V560D were independent of Src family kinases for downstream signaling. However, the independence of Src family kinases was not due to a Src-like kinase activity that c-Kit/D816V displayed. Point mutations that selectively block the association of PI3 kinase with c-Kit/V560D inhibited ligandindependent activation of the receptor, while inhibition of the kinase activity of PI3 kinase with pharmacological inhibitors didn't affect the kinase activity of the receptor. This suggests a lipidkinase independent key role of PI3 kinase in c-Kit/V560D-mediated oncogenic signal transduction. Thus, PI3 kinase is an attractive therapeutic target in malignancies induced by c-Kit mutations independent of its lipid kinase activity.

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The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner

Cited by 16 publications

References 40 publications

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

SOCS6 is a selective suppressor of receptor tyrosine kinase signaling

PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner

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