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, Ravi Salgia

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 gH2AX 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.

Original languageEnglish (US)
Pages (from-to)1820-1835
Number of pages16
JournalMolecular cancer therapeutics
Issue number10
StatePublished - Oct 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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