Paper

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

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

2017

Overview

Purpose: Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors inactivated in ~20% of all cancers. Yet, few targeted treatments for SWI/SNF-mutant cancers exist. 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. Given poor two-year survival rates for these women, a great need exists for effective targeted therapies. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches comprehensively profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two PDX models and one cell line xenograft model of SCCOHT. Results: FGFRs and PDGFRs were overlapping hits between screens and the receptor tyrosine kinase (RTK) family was enriched in the siRNA screen hits. Evaluation of eleven RTK inhibitors in three SCCOHT cell lines identified ponatinib, an inhibitor of multiple RTKs, as the most effective clinically approved agent. Proteomics approaches confirmed inhibition of known targets of ponatinib and more than 20 non-canonical ponatinib targets. Ponatinib also delayed tumor doubling time 4-fold in SCCOHT-1 xenografts and reducing final tumor volumes in two SCCOHT patient-derived xenograft (PDX) models by 58.6% and 42.5%. Conclusion: Ponatinib is an effective agent for 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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Adenosine triphosphatase / Antitumor activity / Cancer Biology / Cell culture / Chromatin remodeling / Drug screening / Genetic screening / Hypercalcemia / Kinases / Menopause / Ovarian cancer / Protein-tyrosine kinase receptors / Proteomics / siRNA / Xenografts