Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers.
Sandra MisaleIvana BozicJingshan TongAshley Peraza-PentonAlice LalloFederica BaldiKevin H LinMauro TruiniLivio TrusolinoAndrea BertottiFederica Di NicolantonioMartin A NowakLin ZhangKris C WoodAlberto BardelliPublished in: Nature communications (2015)
Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.
Keyphrases
- small cell lung cancer
- epidermal growth factor receptor
- tyrosine kinase
- clinical trial
- cell cycle arrest
- induced apoptosis
- pi k akt
- genome wide
- randomized controlled trial
- cell death
- signaling pathway
- endoplasmic reticulum stress
- single cell
- high throughput
- cell proliferation
- high resolution
- single molecule
- double blind
- phase iii