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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
High-throughput drug screening identifies EGFR/MAPK pathway targeting sensitivities in organoid models of ovarian
Andrew Farrell1, Genevieve Dall1,2, Cassandra J Vandenberg1,2
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Background:
Ovarian carcinosarcoma (OCS) is a rare and aggressive tumour type with limited treatment options. Standard therapy includes platinum agents, but responses are poor. OCS highly express mesenchymal markers, such as N-MYC and HMGA2. The microtubule-targeting drug eribulin can reduce expression of N-MYC and HMGA2 in OCS PDX models and functionally reverse EMT in OCS cell lines.
Methods:
In this study, we carried out drug screens in the presence of cisplatin or eribulin to identify synergistic combinations. We validated top combinations in our unique OCS cell line, organoid and PDX models.
Results:
The most effective combination treatments in OCS organoid models involved eribulin, whereas cisplatin-based combination therapies were more effective in high-grade serous ovarian cancer (HGSOC) models. Eribulin combined with either an EGFR inhibitor (erlotinib) or a MEK inhibitor (mirdametinib/PD0325901) were the most effective combinations in OCS models, with a synergistic effect being observed in two (out of four) models for each combination. Mechanistically, OCS models appeared to be particularly reliant on EGFR and MAPK signalling in vitro, especially in tumours with TP53 mutation. In vivo, only modest improvements in survival were observed for eribulin plus erlotinib, however, two of the three OCS PDX models tested were found to have drug resistance mechanisms, such as high ABCB1 expression (encoding the multi-drug resistance protein which causes drug efflux) or a KRAS constitutive activation mutation (a known resistance mechanism to EGFR inhibitors). KRAS mutant OCS cell lines and organoids were sensitive to dual targeting of the EGFR/MAPK pathway, with statistically greater synergy observed when eribulin was added as a third drug.
Conclusions:
OCS is the most aggressive, drug-resistant gynaecological malignancy and eribulin-based combination therapies, particularly triple combination therapies, have the potential to improve patient outcomes.
Insights
Eribulin-based combination therapies show promise for treating aggressive ovarian carcinosarcoma (OCS). Triple combination therapies, particularly with eribulin, erlotinib, and mirdametinib, may improve outcomes for this rare and drug-resistant cancer.
Area of Science:
- Gynecologic Oncology
- Cancer Therapeutics
- Drug Discovery
Background:
- Ovarian carcinosarcoma (OCS) is a rare, aggressive gynecologic malignancy with poor response to standard platinum-based chemotherapy.
- OCS tumors exhibit high expression of mesenchymal markers like N-MYC and HMGA2.
- Eribulin, a microtubule-targeting agent, has shown potential in reducing these markers and reversing epithelial-to-mesenchymal transition (EMT) in OCS models.
Purpose of the Study:
- To identify synergistic drug combinations for ovarian carcinosarcoma (OCS) treatment.
- To evaluate the efficacy of eribulin and cisplatin in combination therapies.
- To validate promising combinations in preclinical OCS models.
Main Methods:
- Conducted drug screens using cisplatin and eribulin in combination.
- Utilized OCS cell lines, organoids, and patient-derived xenograft (PDX) models for validation.
- Investigated underlying resistance mechanisms and signaling pathway dependencies.
Main Results:
- Eribulin-based combinations were most effective in OCS organoid models, while cisplatin combinations were better for high-grade serous ovarian cancer (HGSOC).
- Eribulin combined with EGFR inhibitor erlotinib or MEK inhibitor mirdametinib showed synergistic effects in OCS models.
- Drug resistance mechanisms, including ABCB1 expression and KRAS mutations, were identified in vivo; dual EGFR/MAPK targeting with eribulin demonstrated enhanced synergy in resistant models.
Conclusions:
- Ovarian carcinosarcoma (OCS) represents a highly aggressive and drug-resistant gynecologic cancer.
- Eribulin-based combination therapies, especially triple combinations, offer potential for improved patient outcomes.
- Targeting EGFR and MAPK signaling pathways alongside eribulin may overcome resistance in OCS.
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