TY - JOUR
T1 - ADAMTS16 mutations sensitize ovarian cancer cells to platinumbased chemotherapy
AU - Yasukawa, Maya
AU - Liu, Yuexin
AU - Hu, Limei
AU - Cogdell, David
AU - Gharpure, Kshipra M.
AU - Pradeep, Sunila
AU - Nagaraja, Archana S.
AU - Sood, Anil K.
AU - Zhang, Wei
N1 - Publisher Copyright:
© Yasukawa et al.
PY - 2017
Y1 - 2017
N2 - Ovarian cancer is one of the most lethal malignant tumors in women. The prognosis of ovarian cancer patients depends, in part, on their response to platinumbased chemotherapy. Our recent analysis of genomics and clinical data from the Cancer Genome Atlas demonstrated that somatic mutations of ADAMTS 1, 6, 8, 9, 15, 16, 18 and L1 genes were associated with higher sensitivity to platinum and longer progression-free survival, overall survival, and platinum-free survival duration in 512 patients with high-grade serous ovarian carcinoma. Among the ADAMTS mutations, ADAMTS16 is the most commonly affected gene in ovarian cancer. However, the functional role of these mutations in ovarian cancer cells is largely unknown. We performed in vitro studies to compare the functional effects of the six identified ADAMTS missense mutations on the platinum sensitivity of ovarian cancer cells. We also used a well-characterized in vivo mouse model to evaluate the response of ovarian cancer cells with ADAMTS16 mutations to platinum-based therapy. Our results showed that exogenously expressed ADAMTS16 missense mutations inhibited cell growth or sensitized tumor cells to cisplatin and inhibited tumor growth in vivo. Orthotopic xenograft experiments showed that mice injected with ovarian cancer cells that exogenously expressed ADAMTS16 mutations had a better response to cisplatin treatment. Thus, these functional studies provide evidence that mutations of ADAMTS16 actively contribute to therapeutic response in ovarian cancer.
AB - Ovarian cancer is one of the most lethal malignant tumors in women. The prognosis of ovarian cancer patients depends, in part, on their response to platinumbased chemotherapy. Our recent analysis of genomics and clinical data from the Cancer Genome Atlas demonstrated that somatic mutations of ADAMTS 1, 6, 8, 9, 15, 16, 18 and L1 genes were associated with higher sensitivity to platinum and longer progression-free survival, overall survival, and platinum-free survival duration in 512 patients with high-grade serous ovarian carcinoma. Among the ADAMTS mutations, ADAMTS16 is the most commonly affected gene in ovarian cancer. However, the functional role of these mutations in ovarian cancer cells is largely unknown. We performed in vitro studies to compare the functional effects of the six identified ADAMTS missense mutations on the platinum sensitivity of ovarian cancer cells. We also used a well-characterized in vivo mouse model to evaluate the response of ovarian cancer cells with ADAMTS16 mutations to platinum-based therapy. Our results showed that exogenously expressed ADAMTS16 missense mutations inhibited cell growth or sensitized tumor cells to cisplatin and inhibited tumor growth in vivo. Orthotopic xenograft experiments showed that mice injected with ovarian cancer cells that exogenously expressed ADAMTS16 mutations had a better response to cisplatin treatment. Thus, these functional studies provide evidence that mutations of ADAMTS16 actively contribute to therapeutic response in ovarian cancer.
KW - ADAMTS16
KW - BRCAness
KW - Chemosensitivity
KW - Ovarian cancer
KW - Platinum-based chemotherapy
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U2 - 10.18632/oncotarget.11120
DO - 10.18632/oncotarget.11120
M3 - Article
C2 - 29179445
AN - SCOPUS:85031916481
SN - 1949-2553
VL - 8
SP - 88410
EP - 88420
JO - Oncotarget
JF - Oncotarget
IS - 51
ER -