Abstract 2349: Sensitivity and resistance to cell cycle and IGF-1R inhibitors in rhabdomyosarcoma

Abstract

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. The five-year survival rate for RMS has hardly improved over the last three decades despite intensive and toxic chemotherapy, radiotherapy with surgery. Therefore, novel treatment approaches are required to change these outcomes. RMS has two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS, the more aggressive subtype, is characterized by translocations that fuse two transcription factor-encoding genes; creating novel PAX3/PAX7-FOXO1 fusion proteins. The PAX3-FOXO1 is highly expressed in the G2 phase of the cell cycle, allowing the cell to divide following a sustained checkpoint arrest despite DNA damage induced by chemotherapy, suggesting that PAX3-FOXO1 may enhance the survival of tumor cells in response to chemotherapy. Many cell cycle regulators are altered in RMS, including CDK2, CDK4 and p53. Furthermore, RMS cells are highly dependent on the insulin-like growth factor -1 receptor (IGF-1R) signaling, however, IGF-1R targeting was not successful in the clinic. Therefore, targeting key cell cycle regulators individually or in combination with IGF-1R inhibition may expand the available therapeutic options for RMS. Purpose: The goal of the present study was to investigate the cytotoxicity of 15 small molecule inhibitors targeting the IGF-1R and cell cycle regulators in RMS cell lines and to determine potential mechanisms of drug sensitivity or resistance. Methods and Results: Seven RMS cell lines including ERMS and ARMS were studied. The IC50 values were determined for the following targeting compounds: linsitinib, BMS-754807 and picropodophyllin (PPP) (IGF-1R), riobociclib and palbociclib (CDK4/6), dinaciclib and flavopiridol (pan CDK inhibitors), BS-181HCL (CDK7), MK-1775 (WEE-1), MK-8776 (CHK1), alisertib (AURKA) and volasertib (PLK1). The most potent compounds with IC50< 10 nM were dinaciclib and volasertib. The ARMS cell lines were resistant to alisertib in comparison to the ERMS cell lines. Most cell lines were sensitive to flavopiridol, MK-1775, BMS-754807 and PPP with IC50< 100 nM, and relatively resistant to BS-181 HCL, linsitinib, R0-3306 and MK-8776 with IC50 (1-70 μM). Palbociclib and BMS-754807 showed a synergistic effect in some RMS cell lines. Ongoing studies are focusing on determining the mechanisms of interaction of these two compounds through studying cell cycle, apoptosis, and mRNA and protein expression of key regulators in the IGF-1R and RB pathways. Conclusion: These data demonstrate that dinaciclib, volasertib, flavopiridol, MK-1775, BMS-754807 and PPP are highly cytotoxic in RMS cell lines. The CDK4/6 inhibitor palbociclib may sensitize selected RMS cell lines to IGF-1R inhibitors. Targeting selected cell cycle regulators individually, or in combination with IGF-1R inhibitors may thus provide an efficacious treatment approach to be further validated in RMS patients with poor outcome. Citation Format: Justin Montoya, David W. Lee, Eiman Aleem. Sensitivity and resistance to cell cycle and IGF-1R inhibitors in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2349. doi:10.1158/1538-7445.AM2017-2349