Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to Anti-EGFR therapies in colorectal cancer

Sandra Misale, Sabrina Arena, Simona Lamba, Giulia Siravegna, Alice Lallo, Sebastijan Hobor, Mariangela Russo, Michela Buscarino, Luca Lazzari, Andrea Sartore-Bianchi, Katia Bencardino, Alessio Amatu, Calogero Lauricella, Emanuele Valtorta, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli

Research output: Contribution to journalArticle

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Abstract

Colorectal cancers (CRCs) that are sensitive to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy. We report the emergence of polyclonal KRAS, NRAS, and BRAF mutations in CRC cells with acquired resistance to EGFR blockade. Regardless of the genetic alterations, resistant cells consistently displayed mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) activation, which persisted after EGFR blockade. Inhibition of MEK1/2 alone failed to impair the growth of resistant cells in vitro and in vivo. An RNA interference screen demonstrated that suppression of EGFR, together with silencing of MEK1/2, was required to hamper the proliferation of resistant cells. Indeed, concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells. Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti-EGFR antibodies. A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which reactivate ERK signaling. These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in CRC patients who become refractory to anti-EGFR therapies.

Original languageEnglish
Article number224ra26
JournalScience Translational Medicine
Volume6
Issue number224
DOIs
Publication statusPublished - Feb 19 2014

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Mitogen-Activated Protein Kinase Kinases
Epidermal Growth Factor Receptor
Colorectal Neoplasms
Extracellular Signal-Regulated MAP Kinases
Therapeutics
Mutation
Antibodies
Growth
RNA Interference
Neoplasms
Cell Proliferation
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)

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Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to Anti-EGFR therapies in colorectal cancer. / Misale, Sandra; Arena, Sabrina; Lamba, Simona; Siravegna, Giulia; Lallo, Alice; Hobor, Sebastijan; Russo, Mariangela; Buscarino, Michela; Lazzari, Luca; Sartore-Bianchi, Andrea; Bencardino, Katia; Amatu, Alessio; Lauricella, Calogero; Valtorta, Emanuele; Siena, Salvatore; Di Nicolantonio, Federica; Bardelli, Alberto.

In: Science Translational Medicine, Vol. 6, No. 224, 224ra26, 19.02.2014.

Research output: Contribution to journalArticle

Misale, Sandra ; Arena, Sabrina ; Lamba, Simona ; Siravegna, Giulia ; Lallo, Alice ; Hobor, Sebastijan ; Russo, Mariangela ; Buscarino, Michela ; Lazzari, Luca ; Sartore-Bianchi, Andrea ; Bencardino, Katia ; Amatu, Alessio ; Lauricella, Calogero ; Valtorta, Emanuele ; Siena, Salvatore ; Di Nicolantonio, Federica ; Bardelli, Alberto. / Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to Anti-EGFR therapies in colorectal cancer. In: Science Translational Medicine. 2014 ; Vol. 6, No. 224.
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AU - Lallo, Alice

AU - Hobor, Sebastijan

AU - Russo, Mariangela

AU - Buscarino, Michela

AU - Lazzari, Luca

AU - Sartore-Bianchi, Andrea

AU - Bencardino, Katia

AU - Amatu, Alessio

AU - Lauricella, Calogero

AU - Valtorta, Emanuele

AU - Siena, Salvatore

AU - Di Nicolantonio, Federica

AU - Bardelli, Alberto

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AB - Colorectal cancers (CRCs) that are sensitive to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy. We report the emergence of polyclonal KRAS, NRAS, and BRAF mutations in CRC cells with acquired resistance to EGFR blockade. Regardless of the genetic alterations, resistant cells consistently displayed mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) activation, which persisted after EGFR blockade. Inhibition of MEK1/2 alone failed to impair the growth of resistant cells in vitro and in vivo. An RNA interference screen demonstrated that suppression of EGFR, together with silencing of MEK1/2, was required to hamper the proliferation of resistant cells. Indeed, concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells. Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti-EGFR antibodies. A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which reactivate ERK signaling. These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in CRC patients who become refractory to anti-EGFR therapies.

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