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Clin Cancer Res. 2015 Dec 15;21(24):5499-5510. doi: 10.1158/1078-0432.CCR-14-3091. Epub 2015 Aug 13.

MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer.

Author information

1
Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
2
Molecular Pathology Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
3
Takeda California, San Diego, CA 92121.
4
Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
5
Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.
6
Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, 10060 Candiolo, Torino, Italy.
7
Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
8
Stem Cells and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), 08035-Barcelona, Spain.
9
Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
10
Breast Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
#
Contributed equally

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
26272063
PMCID:
PMC5087596
DOI:
10.1158/1078-0432.CCR-14-3091
[Indexed for MEDLINE]
Free PMC Article

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