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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.

journal_name

Nature

journal_title

Nature

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 CT,Veronese S,Zanon C,Sartore-Bianchi A,Gambacorta M,Gallicchio M,Vakiani E,Boscaro V,

doi

10.1038/nature11156

subject

Has Abstract

pub_date

2012-06-28 00:00:00

pages

532-6

issue

7404

eissn

0028-0836

issn

1476-4687

pii

nature11156

journal_volume

486

pub_type

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