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

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.

SUBMITTER: Mirzapoiazova T

PROVIDER: S-EPMC8722383 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Mirzapoiazova Tamara T Xiao Gang G Mambetsariev Bolot B Nasser Mohd W MW Miaou Emily E Singhal Sharad S SS Srivastava Saumya S Mambetsariev Isa I Nelson Michael S MS Nam Arin A Behal Amita A Arvanitis Leonidas LD Atri Pranita P Muschen Markus M Tissot François L H FLH Miser James J Kovach John S JS Sattler Martin M Batra Surinder K SK Kulkarni Prakash P Salgia Ravi R

Molecular cancer therapeutics 20210712 10

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 <i>in vitro</i> and <i>in vivo</i> with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we de ...[more]

PMID: 34253596

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Dataset Information

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

Publications

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

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