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

Sandra Misale, Rona Yaeger, Sebastijan Hobor, Elisa Scala, Manickam Janakiraman, David Liska, Emanuele Valtorta, Roberta Schiavo, Michela Buscarino, Giulia Siravegna, Katia Bencardino, Andrea Cercek, Chin Tung Chen, Silvio Veronese, Carlo Zanon, Andrea Sartore-Bianchi, Marcello Gambacorta, Margherita Gallicchio, Efsevia Vakiani, Valentina BoscaroEnzo Medico, Martin Weiser, Salvatore Siena, Federica Di Nicolantonio, David Solit, Alberto Bardelli

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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.

Original languageEnglish
Pages (from-to)532-536
Number of pages5
JournalNature
Volume486
Issue number7404
DOIs
Publication statusPublished - Jun 28 2012

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Epidermal Growth Factor Receptor
Colorectal Neoplasms
Mutation
Mitogen-Activated Protein Kinase Kinases
Drug Resistance
Therapeutics
Point Mutation
Documentation
Disease Progression
Cetuximab
Phosphotransferases
Clone Cells
Alleles
Monoclonal Antibodies
Neoplasm Metastasis
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • General

Cite this

Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., Liska, D., ... Bardelli, A. (2012). Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature, 486(7404), 532-536. https://doi.org/10.1038/nature11156

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. / Misale, Sandra; Yaeger, Rona; Hobor, Sebastijan; Scala, Elisa; Janakiraman, Manickam; Liska, David; Valtorta, Emanuele; Schiavo, Roberta; Buscarino, Michela; Siravegna, Giulia; Bencardino, Katia; Cercek, Andrea; Chen, Chin Tung; Veronese, Silvio; Zanon, Carlo; Sartore-Bianchi, Andrea; Gambacorta, Marcello; Gallicchio, Margherita; Vakiani, Efsevia; Boscaro, Valentina; Medico, Enzo; Weiser, Martin; Siena, Salvatore; Di Nicolantonio, Federica; Solit, David; Bardelli, Alberto.

In: Nature, Vol. 486, No. 7404, 28.06.2012, p. 532-536.

Research output: Contribution to journalArticle

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, Medico, E, Weiser, M, Siena, S, Di Nicolantonio, F, Solit, D & Bardelli, A 2012, 'Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer', Nature, vol. 486, no. 7404, pp. 532-536. https://doi.org/10.1038/nature11156
Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012 Jun 28;486(7404):532-536. https://doi.org/10.1038/nature11156
Misale, Sandra ; Yaeger, Rona ; Hobor, Sebastijan ; Scala, Elisa ; Janakiraman, Manickam ; Liska, David ; Valtorta, Emanuele ; Schiavo, Roberta ; Buscarino, Michela ; Siravegna, Giulia ; Bencardino, Katia ; Cercek, Andrea ; Chen, Chin Tung ; Veronese, Silvio ; Zanon, Carlo ; Sartore-Bianchi, Andrea ; Gambacorta, Marcello ; Gallicchio, Margherita ; Vakiani, Efsevia ; Boscaro, Valentina ; Medico, Enzo ; Weiser, Martin ; Siena, Salvatore ; Di Nicolantonio, Federica ; Solit, David ; Bardelli, Alberto. / Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. In: Nature. 2012 ; Vol. 486, No. 7404. pp. 532-536.
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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.",
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AU - Liska, David

AU - Valtorta, Emanuele

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AU - Bencardino, Katia

AU - Cercek, Andrea

AU - Chen, Chin Tung

AU - Veronese, Silvio

AU - Zanon, Carlo

AU - Sartore-Bianchi, Andrea

AU - Gambacorta, Marcello

AU - Gallicchio, Margherita

AU - Vakiani, Efsevia

AU - Boscaro, Valentina

AU - Medico, Enzo

AU - Weiser, Martin

AU - Siena, Salvatore

AU - Di Nicolantonio, Federica

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