MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer.
OBJECTIVE
PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors.


METHODS
In the present study, we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways. Moreover, we investigated if TP53 mutation affects the response to this therapy.


RESULTS
Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell-cycle effects were not affected by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 colorectal cancer models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response toward this combination of agents. A combination response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53 models (two out of five, 40%), but there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of 14 patients with colorectal cancer treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors.


CONCLUSIONS
Our data support that, in wild-type TP53 colorectal cancer cells with ERK and PI3K pathway alterations, MEK blockade results in potent p21 induction, preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK inhibitor-mediated p21 induction, unleashing apoptosis. Clin Cancer Res; 21(24); 5499-510. ©2015 AACR.
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Celina
C
García-García
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Martín A
MA
Rivas
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Yasir H
YH
Ibrahim
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
María Teresa
MT
Calvo
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Albert
A
Gris-Oliver
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Olga
O
Rodríguez
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Judit
J
Grueso
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Pilar
P
Antón
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Marta
M
Guzmán
Molecular Pathology Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Claudia
C
Aura
Molecular Pathology Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Paolo
P
Nuciforo
Takeda California, San Diego, CA 92121.
Katti
K
Jessen
Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
Guillem
G
Argilés
Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
Rodrigo
R
Dienstmann
Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.|Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, 10060 Candiolo, Torino, Italy.
Andrea
A
Bertotti
Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.|Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, 10060 Candiolo, Torino, Italy.
Livio
L
Trusolino
Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Judit
J
Matito
Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Ana
A
Vivancos
Stem Cells and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Irene
I
Chicote
Stem Cells and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Héctor G
HG
Palmer
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.|Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
Josep
J
Tabernero
Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
Maurizio
M
Scaltriti
Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Breast Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
José
J
Baselga
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
Violeta
V
Serra
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; 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; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D046912:Multiprotein Complexes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases