Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma Journal Article
| Authors: | Grbovic-Huezo, O.; Pitter, K. L.; Lecomte, N.; Saglimbeni, J.; Askan, G.; Holm, M.; Melchor, J. P.; Chandwani, R.; Joshi, S.; Haglund, C.; Iacobuzio-Donahue, C. A.; Chiosis, G.; Tammela, T.; Leach, S. D. |
| Article Title: | Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma |
| Abstract: | Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies. © 2020 National Academy of Sciences. All rights reserved. |
| Keywords: | pancreatic cancer | pdac | hsp90 | trametinib | mek |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 117 |
| Issue: | 48 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2020-12-01 |
| Start Page: | 30670 |
| End Page: | 30678 |
| Language: | English |
| DOI: | 10.1073/pnas.1920240117 |
| PUBMED: | 33199632 |
| PROVIDER: | scopus |
| PMCID: | PMC7720119 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 January 2021 -- Source: Scopus |
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