TY - JOUR
T1 - GAS6/AXL Inhibition Enhances Ovarian Cancer Sensitivity to Chemotherapy and PARP Inhibition through Increased DNA Damage and Enhanced Replication Stress
AU - Mullen, Mary M.
AU - Lomonosova, Elena
AU - Toboni, Michael D.
AU - Oplt, Alyssa
AU - Cybulla, Emily
AU - Blachut, Barbara
AU - Zhao, Peinan
AU - Noia, Hollie
AU - Wilke, Daniel
AU - Rankin, Erinn B.
AU - Kuroki, Lindsay M.
AU - Hagemann, Andrea R.
AU - Hagemann, Ian S.
AU - McCourt, Carolyn K.
AU - Thaker, Premal H.
AU - Mutch, David G.
AU - Powell, Matthew A.
AU - Mosammaparast, Nima
AU - Vindigni, Alessandro
AU - Fuh, Katherine
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2022/2
Y1 - 2022/2
N2 - Over 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC.
AB - Over 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC.
UR - http://www.scopus.com/inward/record.url?scp=85124052351&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-21-0302
DO - 10.1158/1541-7786.MCR-21-0302
M3 - Article
C2 - 34670865
AN - SCOPUS:85124052351
SN - 1541-7786
VL - 20
SP - 265
EP - 279
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 2
ER -