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 C.
N1 - Funding Information:
Support for this work was provided by a Reproductive Scientist Development Program award (NICHD 2K12HD000849-28, to K.C. Fuh), a GOG Foundation grant (to M.M. Mullen), and a NCI F30 fellowship (F30C254215, to E. Cybulla). M.M. Mullen holds a Dean’s Scholars Award from the Washington University Division of Physician-Scientists, which is funded by a Burroughs Wellcome Fund Physician-Scientist Institutional Award (1020047). We thank Deborah Frank, PhD and Anthony Bartley for scientific editing and Andrea Byrum, PhD, for technical support.
Funding Information:
L.M. Kuroki reports grants from P50 CA244431, Doris Duke Fund to Retain Clinical Scientists, KL2 TR000450; and nonfinancial support from GOG Foundation New Investigator Award outside the submitted work. I.S. Hagemann reports personal fees from Change Healthcare; and personal fees from serving as an expert witness outside the submitted work. C.K. McCourt reports other support from UpToDate outside the submitted work. P.H. Thaker reports personal fees from Aravive, Seagen, Agenus, Novocure, AstraZeneca, Celsion, Iovance, and Stryker; grants and personal fees from Merck and GlaxoSmithKline; and personal fees from Eisai outside the submitted work. M.A. Powell reports personal fees from Roche/Genetech,
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
VL - 20
SP - 265
EP - 279
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 2
ER -