Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer.
BACKGROUND
The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).


METHODS
The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models.


RESULTS
The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status.


CONCLUSIONS
The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Todd M
TM
Pitts
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Timothy P
TP
Newton
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Erica L
EL
Bradshaw-Pierce
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Rebecca
R
Addison
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
John J
JJ
Arcaroli
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Peter J
PJ
Klauck
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Stacey M
SM
Bagby
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Stephanie L
SL
Hyatt
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Alicia
A
Purkey
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
John J
JJ
Tentler
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Aik Choon
AC
Tan
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Wells A
WA
Messersmith
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
S Gail
SG
Eckhardt
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Stephen
S
Leong
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D004159:Diphenylamine; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C506614:mirdametinib; C546842:MTOR protein, human