title: KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy.
abstract: KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti-EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti-EGFR treatment in a small proportion of patients.
authors: Division of Pathology, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, Milano, Italy.
authors: Emanuele
authors: E
authors: Valtorta
authors: Sandra
authors: S
authors: Misale
authors: Andrea
authors: A
authors: Sartore-Bianchi
authors: Iris D
authors: ID
authors: Nagtegaal
authors: François
authors: F
authors: Paraf
authors: Calogero
authors: C
authors: Lauricella
authors: Valentina
authors: V
authors: Dimartino
authors: Sebastijan
authors: S
authors: Hobor
authors: Bart
authors: B
authors: Jacobs
authors: Cristiana
authors: C
authors: Ercolani
authors: Simona
authors: S
authors: Lamba
authors: Elisa
authors: E
authors: Scala
authors: Silvio
authors: S
authors: Veronese
authors: Pierre
authors: P
authors: Laurent-Puig
authors: Salvatore
authors: S
authors: Siena
authors: Sabine
authors: S
authors: Tejpar
authors: Marcella
authors: M
authors: Mottolese
authors: Cornelis J A
authors: CJ
authors: Punt
authors: Marcello
authors: M
authors: Gambacorta
authors: Alberto
authors: A
authors: Bardelli
authors: Federica
authors: F
authors: Di Nicolantonio
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005784:Gene Amplification; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: EGFR; EGFR therapy; KRAS; KRAS amplification; biomarkers; cetuximab; colorectal cancer; panitumumab; resistance