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00085472can141420-sup-131551_1_supp_2622374_nvmvnh.pptx (87.56 kB)

Supplementary Figure S4 from Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

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posted on 2023-03-30, 22:47 authored by Yoshiaki Chinen, Junya Kuroda, Yuji Shimura, Hisao Nagoshi, Miki Kiyota, Mio Yamamoto-Sugitani, Shinsuke Mizutani, Natsumi Sakamoto, Masaki Ri, Eri Kawata, Tsutomu Kobayashi, Yosuke Matsumoto, Shigeo Horiike, Shinsuke Iida, Masafumi Taniwaki

Supplementary Figure S4. A. BX-912 shows no cross-resistance with BTZ. BX-912 exerted its growth inhibitory effect on BTZ-resistant KMS-11/BTZ cells and OPM-2/BTZ cells (red lines) as effectively as on their respective parental cells (blue dotted lines). Cells were treated with the indicated concentrations of either BX-912 or BTZ for 48 hours. The viable cell number of untreated cells was considered to be 1.0. B. The combination of BX-912 and the NF-κB inhibitor, BAY11-7085, exhibited an additive growth inhibitory effect on BTZ-resistant KMS-11/BTZ cells and OPM-2/BTZ cells. Shaded areas represent the additive effects of the two agents.

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ARTICLE ABSTRACT

Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide–dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma–derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. Cancer Res; 74(24); 7418–29. ©2014 AACR.