Combination targeted treatment may enhance antitumor activity in ERBB3 amplified high-grade serous endometrial cancer cells resistant to single agent targeted therapy
Up-regulation of ERBB pathways represent targetable alterations in many high grade endometrial cancers (EC); ERBB3 amplifications in particular may contribute to ineffective pathway targeting due to persistent co-activation of other ERBB binding partners, leading to tumor growth and survival. The ef...
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Published in | Gynecologic oncology Vol. 162; pp. S114 - S115 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
01.08.2021
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Online Access | Get full text |
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Summary: | Up-regulation of ERBB pathways represent targetable alterations in many high grade endometrial cancers (EC); ERBB3 amplifications in particular may contribute to ineffective pathway targeting due to persistent co-activation of other ERBB binding partners, leading to tumor growth and survival. The efficacy of downstream dual-inhibition of MEK+AKT or MEK+PI3K in an ERBB3 amplified EC primary tumor was studied using a microcancer 3D ex-vivo tumor cell viability assay.
Tumor was prospectively collected from a patient with stage II, FIGO grade 3, serous EC and genomic characterization was performed using multiple sequencing methods: whole exome, RNA, and MatePair analysis. Somatic mutations, structural variance, with transcriptomic profiling was used to identify potential driver pathways for subsequent pharmacologic inhibition. Primary tumor cells were grown in a three-dimensional environment and the formed microcancers were subjected to drug treatment. Cell viability was determined by the CellTiter-Glow Luminescent Assay. Data transformation and dose-response curves were generated using GraphPad PRISM using four parameter logistic regression. CompuSyn software with the Chou-Talalay method was used to analyze drug interactions and synergy. The Fractional response-Combination index (Fa-CI) plot was generated with Microsoft Excel. Capivasertib, GDC-0084, and cobimetinib were used to inhibit AKT, PI3K/mTOR, and MEK, respectively. Inhibitory effect was defined as percent reduction in ATP at clinically-defined predicted plasma maximum concentration (Cmax) values.
Genomic sequencing revealed overexpression of a mutated ERBB3 (c.889G>T; p.Asp297Tyr) transcript within a 6N focal amplification. Additional pertinent alterations included a MYC mid-level gain, and TP53 double hit (loss and exonic splicing silencer (ESS)). Inhibition of cell viability was moderate by single agents: capivasertib, cobimetanib, or GDC-0084, as shown by inhibitory effect values of 33.9%, 35.9% and 49.9%, respectively. Two combinations with cobimetinib demonstrated increasing inhibitory effect values of 76.2% for cobimetanib/capivasertib at the Cmax of capivasertib and 79.7% for cobimetanib/GDC-0084 at the Cmax of cobimetanib. Synergy was evidenced by a combination index <1 at all points with Fa>0.8 (Figure 1).
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Combined inhibition of MEK and PI3K-AKT-mTOR pathways synergistically suppress viability in a patient-derived high-grade serous EC harboring a ERBB3 amplification. Further ex-vivo testing should be performed in endometrial tumors with other ERBB3 aberrations to allow generalization of results. |
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ISSN: | 0090-8258 1095-6859 |
DOI: | 10.1016/S0090-8258(21)00860-X |