# MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition

Source: https://onco.cc/key-papers/paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012/  
OnCo record `paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Triple-negative tumours run high on the MYC oncogene, which predicts poor prognosis, and that dependence makes them vulnerable to CDK inhibitors, which shrank MYC-high tumours in mice.

## Summary

Triple-negative tumours exhibited elevated MYC expression and altered expression of MYC regulatory genes, resulting in increased MYC pathway activity. In primary tumours MYC signalling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. A synthetic-lethal approach dependent on cyclin-dependent kinase inhibition induced regression of triple-negative xenografts; the pro-apoptotic BCL-2 family member BIM was up-regulated after CDK inhibition and contributed to the mechanism.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Journal of Experimental Medicine
- Year: 2012
- DOI: 10.1084/jem.20111512
- Authors: Horiuchi D, Kusdra L, Huskey NE, et al.
- Findings: Elevated MYC expression and pathway activity in TNBC; MYC signalling associated with poor prognosis.; CDK inhibition regressed MYC-high xenografts through BIM up-regulation.
- What it means: MYC amplification, present in a fifth to a third of TNBC, is undruggable directly; this is the synthetic-lethal logic behind CDK (especially CDK9 and CDK1/2) inhibitor trials in the disease.
- Caveats: Preclinical; the pan-CDK inhibitor used is not a clinical agent.; MYC pathway activity was scored by expression signatures rather than amplification alone.

## Sources

- Horiuchi et al., J Exp Med 2012: MYC pathway activation in TNBC is synthetic lethal with CDK inhibition: https://doi.org/10.1084/jem.20111512
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22430491/

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- institutions: [UCSF Helen Diller Family Comprehensive Cancer Center](https://onco.cc/institutions/ucsf/)
- pathways: [MYC](https://onco.cc/pathways/myc/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/), [The cell-cycle engine (cyclins & CDKs)](https://onco.cc/pathways/cell-cycle-engine-cdks/)
- terms: [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- people: [Laura J. Esserman](https://onco.cc/people/laura-esserman/)

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