Oncotarget

Research Papers:

Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer

Alvaro Avivar-Valderas _, Robert McEwen, Amir Taheri-Ghahfarokhi, Larissa S. Carnevalli, Elizabeth L. Hardaker, Marcello Maresca, Kevin Hudson, Elizabeth A. Harrington and Francisco Cruzalegui

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Oncotarget. 2018; 9:21444-21458. https://doi.org/10.18632/oncotarget.25118

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Abstract

Alvaro Avivar-Valderas1,4, Robert McEwen1, Amir Taheri-Ghahfarokhi2, Larissa S. Carnevalli3, Elizabeth L. Hardaker3, Marcello Maresca2, Kevin Hudson3,5, Elizabeth A. Harrington1 and Francisco Cruzalegui1,6

1Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK

2Translational Genomics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

3Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK

4Current address: TiGenix, Parque Tecnológico de Madrid, Tres Cantos, Madrid, Spain

5Current address: 2TheNth, Adelphi Mill, Bollington, Macclesfield, UK

6Current address: Pierre Fabre R&D Centre, Toulouse, France

Correspondence to:

Alvaro Avivar-Valderas, email: alvaro.avivar@tigenix.com

Keywords: luminal A; breast cancer; PIK3CA; MAP3K1; CRISPR gene editing

Received: February 05, 2018    Accepted: March 22, 2018    Published: April 20, 2018

ABSTRACT

The PI3Kα signaling pathway is frequently hyper-activated in breast cancer (BrCa), as a result of mutations/amplifications in oncogenes (e.g. HER2), decreased function in tumor suppressors (e.g. PTEN) or activating mutations in key components of the pathway. In particular, activating mutations of PIK3CA (~45%) are frequently found in luminal A BrCa samples. Genomic studies have uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (~8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples. Further, simultaneous mutation of PIK3CA and MAP3K1 are found in ~11% of mutant PIK3CA tumors. How these two alterations may cooperate to elicit tumorigenesis and impact the sensitivity to PI3K and AKT inhibitors is currently unknown. Using CRISPR gene editing we have genetically disrupted MAP3K1 expression in mutant PIK3CA cell lines to specifically create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1 deficient cell lines exhibited ~2.4-fold increased proliferation rate and decreased sensitivity to PI3Kα/δ(AZD8835) and AKT (AZD5363) inhibitors (~2.61 and ~5.23-fold IC50 increases, respectively) compared with parental control cell lines. In addition, mechanistic analysis revealed that MAP3K1 disruption enhances AKT phosphorylation and downstream signaling and reduces sensitivity to AZD5363-mediated pathway inhibition. This appears to be a consequence of deficient MAP3K1-JNK signaling increasing IRS1 stability and therefore promoting IRS1 binding to p85, resulting in enhanced PI3Kα activity. Using 3D-MCF10A-PI3KαH1047R models, we found that MAP3K1 depletion increased overall acinar volume and counteracted AZD5363-mediated reduction of acinar growth due to enhanced proliferation and reduced apoptosis. Furthermore, in vivo efficacy studies revealed that MAP3K1-deficient MCF7 tumors were less sensitive to AKT inhibitor treatment, compared with parental MCF7 tumors. Our study provides mechanistic and in vivo evidence indicating a role for MAP3K1 as a tumor suppressor gene at least in the context of PIK3CA-mutant backgrounds. Further, our work predicts that MAP3K1 mutational status may be considered as a predictive biomarker for efficacy in PI3K pathway inhibitor trials.


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