Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer Journal Article

   


Authors: Misale, S.; Yaeger, R.; Hobor, S.; Scala, E.; Janakiraman, M.; Liska, D.; Valtorta, E.; Schiavo, R.; Buscarino, M.; Siravegna, G.; Bencardino, K.; Cercek, A.; Chen, C. T.; Veronese, S.; Zanon, C.; Sartore-Bianchi, A.; Gambacorta, M.; Gallicchio, M.; Vakiani, E.; Boscaro, V.; Medico, E.; Weiser, M.; Siena, S.; Di Nicolantonio, F.; Solit, D.; Bardelli, A.
Article Title: Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer
Abstract: A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. © 2012 Macmillan Publishers Limited. All rights reserved.
Keywords: gene mutation; promoter region; mutation; proto-oncogene proteins; cancer growth; colorectal cancer; allele; gene expression; alleles; receptor, epidermal growth factor; drug resistance; drug resistance, neoplasm; cell line, tumor; cetuximab; cancer resistance; panitumumab; colorectal neoplasms; antibodies, monoclonal; promoter regions, genetic; disease progression; radiography; ras proteins; oncogene k ras; genes, ras; point mutation; antibody; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; inhibition; recombinant vasculotropin
Journal Title: Nature
Volume: 486
Issue: 7404
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2012-06-28
Start Page: 532
End Page: 536
Language: English
DOI: 10.1038/nature11156
PROVIDER: scopus
PUBMED: 22722830
PMCID: PMC3927413
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84862999938&partnerID=40&md5=f2f919c3da0c6758da2dea395049e885
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 1 August 2012" - "CODEN: NATUA" - "Source: Scopus"
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MSK Authors
  1. David Solit
    779 Solit
  2. David Liska
    14 Liska
  3. Andrea Cercek Hanjis
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  4. Martin R Weiser
    534 Weiser
  5. Rona Denit Yaeger
    315 Yaeger
  6. Manickam Janakiraman
    33 Janakiraman
  7. Efsevia Vakiani
    263 Vakiani
  8. Chin-Tung Chen
    63 Chen
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