Abstract
Abstract A026: Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer
Cancer research (Chicago, Ill.), Vol.84(5_Supplement_2), pp.A026-A026
03/04/2024
DOI: 10.1158/1538-7445.OVARIAN23-A026
Abstract
Abstract Low-grade serous ovarian cancer (LGSOC) has recently been characterized as a unique subtype of ovarian cancer with distinct molecular characteristics, clinical treatments, and therapeutic responses. Although LGSOC accounts for ~5% of ovarian cancers, the age of onset is younger (~45 years) than other subtypes and has a low response rate (~4%) to the standard of care chemotherapy. One defining characteristic of LGSOC is frequent genetic alterations in the MAPK pathway, which has led to recent MAPK-targeted therapeutic clinical trials. MEK inhibition, particularly with trametinib, has been shown to be effective in patients with recurrent LGSOC (Phase II/III Trial: GOG 281/LOGS). However, these patients eventually develop therapeutic resistance and progressive disease, with no remaining treatment options. Here we sought to characterize the biology of LGSOC and its response to trametinib in an effort to identify candidate mechanisms that may be targeted in combination with trametinib to improve therapeutic efficacy and outcomes for LGSOC patients. After characterizing trametinib responses and identifying cytotoxic doses for a panel of LGSOC cell lines (ES2, OVCAR8, VOA7681, OV7, and OV56), we performed RNA sequencing on each cell line under basal conditions, as well as after 24-hour or 7-day exposure to an IC95 dose of trametinib. These experiments identified both acute and longer-term transcriptional changes that occur in response to trametinib. CRISPR screens targeting the kinome were also performed to identify synthetic lethal interactions between trametinib treatment and loss of function of specific protein kinases. Integrated analysis of these approaches identified several potential candidates (AKT, mTOR, CDKs, among others) that may be targeted in combination with trametinib to improve LGSOC patient outcomes. Experiments testing synergistic relationships between trametinib and other FDA approved inhibitors were performed. Using these combination therapeutic approaches could re-sensitize cells to trametinib treatment or prevent the emergence of resistance, thereby improving therapeutic efficacy. If successful, a similar approach could be used in a clinical trial to treat patients with LGSOC. Citation Format: Rebekah M. Peplinski, Silvana Pedra Nobre, Jacob L. Schillo, Keely K. Ulmer, Yasmin A. Lyons, Jesse D. Riordan, Michael J. Goodheart, Adam J. Dupuy. Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A026.
Details
- Title: Subtitle
- Abstract A026: Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer
- Creators
- Rebekah M. Peplinski - University of IowaSilvana Pedra NobreJacob L. Schillo - University of IowaKeely K. Ulmer - University of IowaYasmin A. Lyons - University of IowaJesse D. Riordan - University of IowaMichael J. Goodheart - University of IowaAdam J. Dupuy - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.84(5_Supplement_2), pp.A026-A026
- DOI
- 10.1158/1538-7445.OVARIAN23-A026
- ISSN
- 1538-7445
- eISSN
- 1538-7445
- Language
- English
- Date published
- 03/04/2024
- Academic Unit
- Pathology; Epidemiology; Obstetrics and Gynecology; Anatomy and Cell Biology
- Record Identifier
- 9984648359302771
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