Research ArticleCancer

Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR

See allHide authors and affiliations

Science Signaling  11 Nov 2014:
Vol. 7, Issue 351, pp. ra107
DOI: 10.1126/scisignal.2005516

You are currently viewing the editor's summary.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Drug Resistance Reveals Vulnerability

Kinase inhibitors are a common therapy for many cancers, but tumors frequently acquire resistance. Understanding the mechanisms of resistance can reveal new therapeutic options. Using various human and mouse models of KRAS-mutant colorectal cancer (CRC), Belmont et al. found that signaling by the receptor tyrosine kinase EGFR and the related ERBB family members was increased in CRC cells that had acquired resistance to a dual inhibitor of the kinases PI3K and mTOR. Increased EGFR expression was induced by the drug through the release of PI3K pathway–mediated inhibition of the transcription factor FOXO3a. Withdrawing the drug from culture medium returned EGFR abundance and signaling to pretreatment levels. Inhibiting EGFR restored sensitivity to the PI3K/mTOR inhibitor in drug-resistant cells in culture and induced tumor regression in drug-resistant allografts in mice. Thus, CRC patients that develop resistance to PI3K/mTOR inhibitors may benefit from additional treatment with EGFR inhibitors.

View Full Text

Stay Connected to Science Signaling