TY - JOUR
T1 - Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition
AU - Lang, Jessica D.
AU - Hendricks, William P.D.
AU - Orlando, Krystal A.
AU - Yin, Hongwei
AU - Kiefer, Jeffrey
AU - Ramos, Pilar
AU - Sharma, Ritin
AU - Pirrotte, Patrick
AU - Raupach, Elizabeth A.
AU - Sereduk, Chris
AU - Tang, Nanyun
AU - Liang, Winnie S.
AU - Washington, Megan
AU - Facista, Salvatore J.
AU - Zismann, Victoria L.
AU - Cousins, Emily M.
AU - Major, Michael B.
AU - Wang, Yemin
AU - Karnezis, Anthony N.
AU - Sekulic, Aleksandar
AU - Hass, Ralf
AU - Vanderhyden, Barbara C.
AU - Nair, Praveen
AU - Weissman, Bernard E.
AU - Huntsman, David G.
AU - Trent, Jeffrey M.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.
AB - Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.
UR - http://www.scopus.com/inward/record.url?scp=85047872502&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047872502&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-1928
DO - 10.1158/1078-0432.CCR-17-1928
M3 - Article
C2 - 29440177
AN - SCOPUS:85047872502
SN - 1078-0432
VL - 24
SP - 1932
EP - 1943
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -