Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging.
K-ras is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), the most common form of lung cancer. Recent studies indicate that NSCLC patients with mutant K-ras do not respond to epidermal growth factor receptor inhibitors. In the attempt to find alternative therapeutic regimes for such patients, we tested PHA-848125, an oral pan cyclin-dependent kinase inhibitor currently under evaluation in phase II clinical trial, on a transgenic mouse model, K-Ras(G12D)LA2, which develops pulmonary cancerous lesions reminiscent of human lung adenocarcinomas. We used magnetic resonance imaging and positron emission tomography to follow longitudinally disease progression and evaluate therapeutic efficacy in this model. Treatment of K-Ras(G12D)LA2 mice with 40 mg/kg twice daily for 10 days with PHA-848125 induced a significant tumor growth inhibition at the end of treatment (P < 0.005) and this was accompanied by a reduction in the cell membrane turnover, as seen by 11C-Choline-positron emission tomography (P < 0.05). Magnetic resonance imaging data were validated versus histology and the mechanism of action of the compound was verified by immunohistochemistry, using cyclin-dependent kinase-related biomarkers phospho-Retinoblastoma and cyclin A. In this study, multimodality imaging was successfully used for the preclinical assessment of PHA-848125 therapeutic efficacy on a lung adenocarcinoma mouse model. This compound induced a volumetric and metabolic anticancer effect and could represent a valid therapeutic approach for NSCLC patients with mutant K-ras.
Degrassi
Anna
A
Pharmacology Department, BU Oncology, Nerviano Medical Sciences, Milano, Italy. Anna.Degrassi@nervianoms.com
Russo
Micaela
M
Nanni
Cristina
C
Patton
Veronica
V
Alzani
Rachele
R
Giusti
Anna M
AM
Fanti
Stefano
S
Ciomei
Marina
M
Pesenti
Enrico
E
Texido
Gemma
G
D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003952:Diagnostic Imaging / Q000379:methods* / Q000662:veterinary; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D011905:Genes, ras; D005998:Glycine / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D050505:Mutant Proteins; C550092:N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide; D011720:Pyrazoles; D011799:Quinazolines; D001224:Aspartic Acid; D018844:Cyclin-Dependent Kinases; D005998:Glycine