Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition

Jessica D. Lang, William P.D. Hendricks, Krystal A. Orlando, Hongwei Yin, Jeffrey Kiefer, Pilar Ramos, Ritin Sharma, Patrick Pirrotte, Elizabeth A. Raupach, Chris Sereduk, Nanyun Tang, Winnie S. Liang, Megan Washington, Salvatore J. Facista, Victoria L. Zismann, Emily M. Cousins, Michael B. Major, Yemin Wang, Anthony Karnezis, Aleksandar SekulicRalf Hass, Barbara C. Vanderhyden, Praveen Nair, Bernard E. Weissman, David G. Huntsman, Jeffrey M. Trent

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1932-1943
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number8
DOIs
StatePublished - Apr 15 2018
Externally publishedYes

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Small Cell Carcinoma
Ovary
Heterografts
Receptor Protein-Tyrosine Kinases
Small Interfering RNA
Phosphotransferases
Cell Line
Pharmaceutical Preparations
Proteomics
Ovarian Neoplasms
ponatinib
Tumor Burden
Adenosine Triphosphatases
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition. / Lang, Jessica D.; Hendricks, William P.D.; Orlando, Krystal A.; Yin, Hongwei; Kiefer, Jeffrey; Ramos, Pilar; Sharma, Ritin; Pirrotte, Patrick; Raupach, Elizabeth A.; Sereduk, Chris; Tang, Nanyun; Liang, Winnie S.; Washington, Megan; Facista, Salvatore J.; Zismann, Victoria L.; Cousins, Emily M.; Major, Michael B.; Wang, Yemin; Karnezis, Anthony; Sekulic, Aleksandar; Hass, Ralf; Vanderhyden, Barbara C.; Nair, Praveen; Weissman, Bernard E.; Huntsman, David G.; Trent, Jeffrey M.

In: Clinical Cancer Research, Vol. 24, No. 8, 15.04.2018, p. 1932-1943.

Research output: Contribution to journalArticle

Lang, JD, Hendricks, WPD, Orlando, KA, Yin, H, Kiefer, J, Ramos, P, Sharma, R, Pirrotte, P, Raupach, EA, Sereduk, C, Tang, N, Liang, WS, Washington, M, Facista, SJ, Zismann, VL, Cousins, EM, Major, MB, Wang, Y, Karnezis, A, Sekulic, A, Hass, R, Vanderhyden, BC, Nair, P, Weissman, BE, Huntsman, DG & Trent, JM 2018, 'Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition', Clinical Cancer Research, vol. 24, no. 8, pp. 1932-1943. https://doi.org/10.1158/1078-0432.CCR-17-1928
Lang, Jessica D. ; Hendricks, William P.D. ; Orlando, Krystal A. ; Yin, Hongwei ; Kiefer, Jeffrey ; Ramos, Pilar ; Sharma, Ritin ; Pirrotte, Patrick ; Raupach, Elizabeth A. ; Sereduk, Chris ; Tang, Nanyun ; Liang, Winnie S. ; Washington, Megan ; Facista, Salvatore J. ; Zismann, Victoria L. ; Cousins, Emily M. ; Major, Michael B. ; Wang, Yemin ; Karnezis, Anthony ; Sekulic, Aleksandar ; Hass, Ralf ; Vanderhyden, Barbara C. ; Nair, Praveen ; Weissman, Bernard E. ; Huntsman, David G. ; Trent, Jeffrey M. / Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 8. pp. 1932-1943.
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abstract = "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.",
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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

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.

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.

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