TY - JOUR
T1 - Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer
AU - Mirzapoiazova, Tamara
AU - Xiao, Gang
AU - Mambetsariev, Bolot
AU - Nasser, Mohd W.
AU - Miaou, Emily
AU - Singhal, Sharad S.
AU - Srivastava, Saumya
AU - Mambetsariev, Isa
AU - Nelson, Michael S.
AU - Nam, Arin
AU - Behal, Amita
AU - Atri, Pranita
AU - Muschen, Markus
AU - Tissot, François L.H.
AU - Miser, James
AU - Kovach, John S.
AU - Sattler, Martin
AU - Batra, Surinder K.
AU - Kulkarni, Prakash
AU - Salgia, Ravi
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-21-0013
DO - 10.1158/1535-7163.MCT-21-0013
M3 - Article
C2 - 34253596
AN - SCOPUS:85117732899
SN - 1535-7163
VL - 20
SP - 1820
EP - 1835
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 10
ER -