Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-12, Vol.117 (48), p.30670-30678
• Main Authors: Grbovic-Huezo, Olivera, Pitter, Kenneth L., Lecomte, Nicolas, Saglimbeni, Joseph, Askan, Gokce, Holm, Matilda, Melchor, Jerry P., Chandwani, Rohit, Joshi, Suhasini, Haglund, Caj, Iacobuzio-Donahue, Christine A., Chiosis, Gabriela, Tammela, Tuomas, Leach, Steven D.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - pathology; AKT protein; Animal models; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor agents; Benzodioxoles - pharmacology; Biocompatibility; Biological Sciences; Biomarkers, Tumor; Cell Line, Tumor; Chemotherapy; Disease Models, Animal; Drug development; Drug Evaluation, Preclinical - methods; Drug Screening Assays, Antitumor - methods; Drug Synergism; Gene Expression; Heat shock proteins; Hsp90 protein; Humans; Immunohistochemistry; MAP Kinase Signaling System - drug effects; Medical prognosis; Mice; Molecular Targeted Therapy; Organoids; Pancreas; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Pyridones - pharmacology; Pyrimidinones - pharmacology; Signal Transduction - drug effects; Survival Rate; Therapeutic targets; Therapy; TOR protein; Toxicity; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1920240117

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.