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01-09-2019 | Breast Cancer | Preclinical study

Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway

Authors: Sanja B. Turturro, Matthew S. Najor, Timothy Yung, Liam Portt, Christopher S. Malarkey, Abde M. Abukhdeir, Melody A. Cobleigh

Published in: Breast Cancer Research and Treatment | Issue 2/2019

Abstract

Purpose

The PI3K pathway, which includes the PI3K catalytic subunits p110α (PIK3CA) and the PI3K regulatory subunit p85α (PIK3R1), is the most frequently altered pathway in cancer. We encountered a breast cancer patient whose tumor contained a somatic alteration in PIK3R1. Some commercial sequencing platforms suggest that somatic mutations in PIK3R1 may sensitize cancers to drugs that inhibit the mammalian target of rapamycin (mTOR). However, a review of the preclinical and clinical literature did not find evidence substantiating that hypothesis. The purpose of this study was to knock out PIK3R1 in order to determine the optimal therapeutic approach for breast cancers lacking p85α.

Methods

We created an isogenic cellular system by knocking out both alleles of the PIK3R1 gene in the non-tumorigenic human breast cell line MCF-10A. Knockout cells were compared with wild-type cells by measuring growth, cellular signaling, and response to drugs.

Results

We observed hyperphosphorylation of MEK in these knockouts, which sensitized PIK3R1-null cells to a MEK inhibitor, trametinib. However, they were not sensitized to the mTOR inhibitor, everolimus.

Conclusions

Our findings suggest that breast cancers with loss of p85α may not respond to mTOR inhibition, but may be sensitive to MEK inhibition.

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Title: Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway
Authors: Sanja B. Turturro
Matthew S. Najor
Timothy Yung
Liam Portt
Christopher S. Malarkey
Abde M. Abukhdeir
Melody A. Cobleigh
Publication date: 01-09-2019
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Everolimus
Published in: Breast Cancer Research and Treatment / Issue 2/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05320-x

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