title: Ras-induced resistance to lapatinib is overcome by MEK inhibition.
abstract: Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor is highly active in HER2+ breast cancer. However, its efficacy is limited by either primary or acquired resistance. Although mutations in ras genes are rarely found in breast cancer, H-ras overexpression is frequently observed. Moreover, genetic alterations that do not directly involve ras such as Brk amplification, ultimately result in increased ras signaling. Using SKBR3 cells, a HER2+ breast cancer cell line that is naturally devoid of mutations in PI3KCA, PTEN, BRAF, and ras we show that both H-ras overexpression and expression of an oncogenic ras allele (ras V12) reduce susceptibility to lapatinib in analogy to what observed with activating PI3KCA mutations and with a constitutively active form of Akt. Importantly, we found that resistance to lapatinib due to ras overexpression or to ras V12 is overcome by MEK inhibition with U0126, suggesting a key role for the MEK-Erk pathway in ras-induced resistance. Similar results were obtained in BT474 cells, another HER+ breast cancer cell line. Therefore, our data indicate that overexpressed/mutated ras may act as a biological modifier of the response to lapatinib. Combining MEK inhibitors with lapatinib may help overcome this form of resistance and increase the efficacy of lapatinib in these tumors.
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zoppoli
authors.forename: Eva
authors.initials: E
authors.lastname: Moran
authors.forename: Debora
authors.initials: D
authors.lastname: Soncini
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.forename: Anna
authors.initials: A
authors.lastname: Garuti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rocco
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cirmena
authors.forename: Valentina
authors.initials: V
authors.lastname: Grillo
authors.forename: Luca
authors.initials: L
authors.lastname: Bagnasco
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Icardi
authors.forename: Filippo
authors.initials: F
authors.lastname: Ansaldi
authors.forename: Silvio
authors.initials: S
authors.lastname: Parodi
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D011905:Genes, ras / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D000077341:Lapatinib; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D000077341:Lapatinib; D020929:Mitogen-Activated Protein Kinase Kinases; D009570:Nitriles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C113580:U 0126; C508053:ERBB2 protein, human