Unbiased Compound Screening Identifies Unexpected Drug Sensitivities and Novel Treatment Options for Gastrointestinal Stromal Tumors

Abstract

Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)-approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDAapproved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration. Cancer Res; 74(4); 1200-13. Ó2014 AACR.

Establishment of the Clone of Gastrointestinal Stromal Tumor Cells with the Signs of Multiple Drug Resistance and Assessment of Its Properties

“…For example, it was shown rather good perspectives of some chemotherapeutic drugs to manage the patients with metastatic and inoperable forms of GIST [3,4]. The results obtained by our research group also demonstrate that some GIST cell lines are sensitive to the topoisomerase type II inhibitors in vitro and in vivo [5,6]. Of note, the chemotherapeutic drugs indicated above were found to be effective against both types of GIST cell lines known to be sensitive and resistant to the targeted therapy by imatinib.…”

Targeting ETV1 in Gastrointestinal Stromal Tumors: Tripping the Circuit Breaker in GIST?

“…In addition, this study has shown once more how important it is to identify additional therapeutic options for patients with GIST that make use of these tumors' specifi c molecular makeup aside from KIT/ PDGFRA mutations. Especially targeting the transcriptional machinery-either globally or with the aim of reducing the expression levels of specifi c genes (such as KIT and ETV1 )-has recently emerged as an important new angle for the treatment of GIST and other oncogene-driven malignancies (8)(9)(10). For example, inhibitors of the 26S proteasome, such as bortezomib (Velcade), have been shown to inhibit ongoing gene transcription in GIST, leading to a dramatic loss of KIT protein expression and subsequent apoptosis ( 8 ).…”

“…The SP1 inhibitor mithramycin A, a "classical" transcriptional inhibitor, has recently gained attention again for being the top hit in a 50,000 compound screen against the EWS-FLI1 fusion oncogene in Ewing family sarcoma ( 9 ). It was also identifi ed in a smaller library screen as being effective for GISTs, with its main mechanism of action lying in the reduction of KIT ( 10 ). Specifi cally in GIST, targeting gene transcription and its regulators allows the bypass of secondary KIT/PDGFRA mutations that emerge during tyrosine kinase inhibitor treatment, thus paving the way to a more complete eradication of tumor cells.…”

Imatinib enchances the sensitivity of gastrointestinal stromal tumors to topoisomerase II inhibitors

“…Тем не менее результаты проведенных нами ранее исследований показали, что некоторые химиопрепа-раты могут быть эффективными по отношению к кле-точным линиям ГИСО in vitro [9]. Примечательно, что данный эффект химиопрепаратов был выявлен как в отношении иматиниб-чувствительных, так и ре-зистентных к иматинибу клеточных линий ГИСО.…”