Editors' ChoiceCancer

Personalized medicine finds the MAPK for breast cancer

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Science Translational Medicine  20 Dec 2017:
Vol. 9, Issue 421, eaar4440
DOI: 10.1126/scitranslmed.aar4440

Abstract

Whole-exome sequencing and RNA-seq on a mouse model of triple-negative breast cancer reveal actionable therapeutic targets for precision medicine guided treatment.

All tumors harbor points of fragility, but these differ between tumor types and, most importantly, between patients. The goal of personalized medicine is to uncloak the key pathways that each individual tumor depends on for survival and design treatment strategies accordingly. However, in some tumors, such as triple-negative breast cancer (TNBC), targetable oncogenic pathways are rarely altered, making the strategy of personalized therapy a challenge. In an effort to overcome this, Liu et al. established a genetically engineered mouse model that recapitulates human TNBC and interrogated the genetics of resulting tumors to establish an approach that can inform the use of approved or experimental drugs to treat individual TNBC patients.

To generate a representative model of human TNBC, the authors disrupted the activity of proteins commonly found mutated in this cancer. Specifically, they deleted the tumor suppressor p53 only in the breast, either alone, or also with deletion of BRCA1, which is commonly mutated in breast cancer. The resulting mice developed breast tumors that had the pathology and transcriptional signature of human TNBC. Then, they used whole-exome sequencing and RNA sequencing in an attempt to identify previously unidentified oncogenic drivers of these tumors. This approach revealed chromosomal rearrangements that led to a diversity of amplifications and fusions of oncogenic drivers. Although the specific genetic aberrations differed between tumors overall, as well as between tumors that had or did not have BRCA1 loss, a common theme emerged for what signaling pathways were ultimately altered in the tumors. Namely, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways were activated. These signaling nodes are commonly altered in cancers to help the tumors grow and survive, but targeting these pathways is highly toxic. Knowing this, the authors took the approach of using small molecule inhibitors that specifically targeted the upstream amplification and fusion events and were able to demonstrate therapeutic efficacy in the models. Last, to correlate the findings from their mouse model to human disease, they queried available databases and identified that genetic changes leading to MAPK/PI3K activation are also common in human TNBC.

This work underscores that personalized medicine strategies are achievable even for tumors that don’t harbor common mutations in oncogenic drivers. The hurdle still remains to bring individual tumor screening as standard of care for all cancers, but as clinical trials designed to do just that are currently ongoing, these studies provide strong rationale for the utility of this approach.

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