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Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer

Mirzapoiazova, Tamara and Xiao, Gang and Mambetsariev, Bolot and Nasser, Mohd W. and Miaou, Emily and Singhal, Sharad S. and Srivastava, Saumya and Mambetsariev, Isa and Nelson, Michael S. and Nam, Arin and Behal, Amita and Atri, Pranita and Müschen, Markus and Tissot, François L. H. and Miser, James and Kovach, John S. and Sattler, Martin and Batra, Surinder K. and Kulkarni, Prakash and Salgia, Ravi (2021) Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer. Molecular Cancer Therapeutics, 20 (10). pp. 1820-1835. ISSN 1535-7163. doi:10.1158/1535-7163.MCT-21-0013. https://resolver.caltech.edu/CaltechAUTHORS:20210730-171053099

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Abstract

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both in vitro and in vivo with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells. Treatment with LB100 alone or in combination resulted in inhibition of cell viability in two-dimensional culture and three-dimensional spheroid models of SCLC, reduced glucose uptake, and attenuated mitochondrial and glycolytic ATP production. Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids, and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX and enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1158/1535-7163.mct-21-0013DOIArticle
ORCID:
AuthorORCID
Mirzapoiazova, Tamara0000-0001-9353-229X
Xiao, Gang0000-0002-9476-3847
Nasser, Mohd W.0000-0003-2070-4972
Singhal, Sharad S.0000-0002-6415-8160
Mambetsariev, Isa0000-0003-2882-0249
Nelson, Michael S.0000-0003-0480-5597
Atri, Pranita0000-0002-0417-0256
Müschen, Markus0000-0002-6064-8613
Tissot, François L. H.0000-0001-6622-2907
Miser, James0000-0003-1881-251X
Sattler, Martin0000-0001-5053-4199
Batra, Surinder K.0000-0001-9470-9317
Salgia, Ravi0000-0001-9643-7626
Additional Information:© 2021 The Author(s). This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License. Received January 8, 2021. Revision received April 22, 2021. Accepted July 7, 2021. Published first July 12, 2021. The work was supported by the NCI of the NIH under award numbers P30CA033572, U54CA209978, R01CA247471, and R01CA218545. We thank Andrea Bild and Pierre Wallet, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, for experimental advice and for the reagents, and the City of Hope Light Microscopy Core, High Throughput Screening Core and Pathology, Solid Tumor Core, for help with sample processing. The murine SCLC cell lines C2.04, C896.04, and C22.03 were a generous gift from Dr. Anton Berns' lab. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
NIHP30CA033572
NIHU54CA209978
NIHR01CA247471
NIHR01CA218545
Subject Keywords:Small cell Lung cancer, Protein Phosphatase 2A, LB100, Carboplatin, Combination therapy
Issue or Number:10
DOI:10.1158/1535-7163.MCT-21-0013
Record Number:CaltechAUTHORS:20210730-171053099
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210730-171053099
Official Citation:Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer. Tamara Mirzapoiazova, Gang Xiao, Bolot Mambetsariev, Mohd W. Nasser, Emily Miaou, Sharad S. Singhal, Saumya Srivastava, Isa Mambetsariev, Michael S. Nelson, Arin Nam, Amita Behal, Pranita Atri, Markus Muschen, François L.H. Tissot, James Miser, John S. Kovach, Martin Sattler, Surinder K. Batra, Prakash Kulkarni and Ravi Salgia. Mol Cancer Ther October 1 2021 (20) (10) 1820-1835; DOI: 10.1158/1535-7163.MCT-21-0013
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110101
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Aug 2021 15:55
Last Modified:04 Oct 2021 22:21

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