TY - JOUR
T1 - An oligoclonal antibody durably overcomes resistance of lung cancer to third-generation EGFR inhibitors
AU - Mancini, Maicol
AU - Gal, Hilah
AU - Gaborit, Nadege
AU - Mazzeo, Luigi
AU - Romaniello, Donatella
AU - Salame, Tomer Meir
AU - Lindzen, Moshit
AU - Mahlknecht, Georg
AU - Enuka, Yehoshua
AU - Burton, Dominick G. A.
AU - Roth, Lee
AU - Noronha, Ashish
AU - Marrocco, Ilaria
AU - Adreka, Dan
AU - Altstadter, Raya Eilam
AU - Bousquet, Emilie
AU - Downward, Julian
AU - Maraver, Antonio
AU - Krizhanovsky, Valery
AU - Yarden, Yosef
N1 - We thank Michael Sela for continuous help and Alon Harmelin, Inbal Biton, Nava Nevo, Ori Brenner, and Naama Feldman for guiding our animal studies. Our laboratory was supported by the European Research Council, the Israel Science Foundation, the Seventh Framework Program of the European Commission (Lung Target Consortium), the Israel Cancer Research Fund and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. Our studies were performed in the Marvin Tanner Laboratory for Research on Cancer. Author contributions: MM and YY designed the study; MM, HG, NG, LM, DR, TMS, ML, GM, YE, DGAB, LR, AN, IM, and REA performed the experiments; MM, VK, DA, and YY analyzed data; EB, JD, and AM provided reagents; MM, VK, and YY wrote the manuscript.
PY - 2018/2
Y1 - 2018/2
N2 - Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3xmAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors. We now report that 3xmAbs, including a triplet containing cetuximab and trastuzumab, inhibits C797S-expressing tumors. Unlike osimertinib, which induces apoptosis, 3xmAbs promotes degradation of the three receptors and induces cellular senescence. Consistent with distinct mechanisms, treatments combining 3xmAbs plus sub-inhibitory doses of osimertinib synergistically and persistently eliminated tumors. Thus, oligoclonal antibodies, either alone or in combination with kinase inhibitors, might preempt repeated cycles of treatment and rapid emergence of resistance.
AB - Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3xmAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors. We now report that 3xmAbs, including a triplet containing cetuximab and trastuzumab, inhibits C797S-expressing tumors. Unlike osimertinib, which induces apoptosis, 3xmAbs promotes degradation of the three receptors and induces cellular senescence. Consistent with distinct mechanisms, treatments combining 3xmAbs plus sub-inhibitory doses of osimertinib synergistically and persistently eliminated tumors. Thus, oligoclonal antibodies, either alone or in combination with kinase inhibitors, might preempt repeated cycles of treatment and rapid emergence of resistance.
U2 - 10.15252/emmm.201708076
DO - 10.15252/emmm.201708076
M3 - مقالة
SN - 1757-4676
VL - 10
SP - 294
EP - 308
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 2
ER -