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.
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.
Oncology Research Unit, Pfizer Global R&D, San Diego, CA 92121, USA.
Brett H
BH
Simmons
Joseph H
JH
Lee
Kush
K
Lalwani
Anand
A
Giddabasappa
Brittany A
BA
Snider
Anthony
A
Wong
Patrick B
PB
Lappin
Jeetendra
J
Eswaraka
Julie L
JL
Kan
James G
JG
Christensen
Farbod
F
Shojaei
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D006579:Heterozygote; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D020714:Maximum Tolerated Dose; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D001549:Benzamides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C506614:mirdametinib; D004159:Diphenylamine; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)