title: Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.
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.
authors.affiliation: Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Misale
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.forename: Alice
authors.initials: A
authors.lastname: Lallo
authors.forename: Sebastijan
authors.initials: S
authors.lastname: Hobor
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.forename: Michela
authors.initials: M
authors.lastname: Buscarino
authors.forename: Luca
authors.initials: L
authors.lastname: Lazzari
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Katia
authors.initials: K
authors.lastname: Bencardino
authors.forename: Alessio
authors.initials: A
authors.lastname: Amatu
authors.forename: Calogero
authors.initials: C
authors.lastname: Lauricella
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases