Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice.

Abstract

The role of PI3K and MAPK pathways in tumor initiation and progression is well established; hence, several inhibitors of these pathways are currently in different stages of clinical trials. Recent studies identified a PI3K/mTOR (PF-04691502) and a MEK inhibitor (PD-0325901) with strong potency and efficacy in different cell lines and tumor models. PD-0325901, however, showed adverse effects when administered at or above MTD (maximum tolerated dose) in the clinic. Here, we show in preclinical models that PD-0325901 at doses well below MTD (sub-MTD 1.5 mg/kg SID) is still a potent compound as single agent or in combination with PF-04691502. We first observed that PD-0325901 at 1.5 mg/kg SID and in combination with PF-04691502 (7.5 mg/kg; SID) significantly inhibited growth of H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors. Additionally, we tested efficacy of PD-0325901 in Kras(G12D-LSL) conditional GEMMs (genetically engineered mouse models) which are a valuable tool in translational research to study tumor progression. Intranasal delivery of adenoviruses expressing Cre recombinase (Adeno-Cre) resulted in expression of mutant Kras leading to development of tumor lesions in lungs including adenomatous hyperplasia, large adenoma, and adenocarcinoma. Similar to H460 tumors, PD-0325901 as single agent or in combination with PF-04691502 significantly inhibited growth of tumor lesions in lungs in Kras(G12D-LSL) mice when treatment started at adenocarcinoma stage (at 14 weeks post-Adeno-Cre inhalation). In addition, immunohistochemistry showed inhibition of pS6 (phosphorylated ribosomal S6) in the treated animals particularly in the combination group providing a proof of mechanism for tumor growth inhibition. Finally, m-CT imaging in live Kras(G12D-LSL) mice showed reduction of tumor burdens in PD-0325901-treated animals at sub-MTD dose. In conclusion, our data suggest that PD-0325901 at doses below MTD is still a potent compound capable of tumor growth inhibition where Kras and/or PI3K are drivers of tumor growth and progression.

• Authors: Brett H Simmons, Joseph H Lee, Kush Lalwani, Anand Giddabasappa, Brittany A Snider, Anthony Wong, Patrick B Lappin, Jeetendra Eswaraka, Julie L Kan, James G Christensen, Farbod Shojaei
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 70 Issue 2 Pg. 213-20 (Aug 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22684718 (Publication Type: Journal Article)

Chemical References

• 2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
• Benzamides
• Phosphoinositide-3 Kinase Inhibitors
• Pyridones
• Pyrimidines
• mirdametinib
• Diphenylamine
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase Kinases
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Adenocarcinoma (drug therapy, enzymology)
• Adenocarcinoma of Lung
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Benzamides (administration & dosage)
• Cell Line, Tumor
• Diphenylamine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Heterozygote
• Humans
• Lung Neoplasms (drug therapy, enzymology)
• Maximum Tolerated Dose
• Mice
• Mice, Mutant Strains
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Neoplasm Transplantation
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins p21(ras) (genetics)
• Pyridones (administration & dosage)
• Pyrimidines (administration & dosage)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)