TY - JOUR
T1 - Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models
AU - Marrocco, Ilaria
AU - Romaniello, Donatella
AU - Vaknin, Itay
AU - Drago-Garcia, Diana
AU - Oren, Roni
AU - Uribe, Mary Luz
AU - Belugali Nataraj, Nishanth
AU - Ghosh, Soma
AU - Eilam, Raya
AU - Salame, Tomer Meir
AU - Lindzen, Moshit
AU - Yarden, Yosef
N1 - Funding Information:
We thank all members of our laboratory for their kind help and insightful comments. IM and DR would like to thank the Lombroso Foundation for their fellowships. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies are supported by the European Research Council (ERC) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
Funding Information:
We thank all members of our laboratory for their kind help and insightful comments. IM and DR would like to thank the Lombroso Foundation for their fellowships. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies are supported by the European Research Council (ERC) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/4/9
Y1 - 2021/4/9
N2 - Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti-cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first-, second-, and third-generation drugs. To explore alternatives to such whack-a-mole strategies, we simulated in patient-derived xenograft models the situation of patients receiving first-line TKIs. Monotherapies comprising approved first-line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance-conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next-generation TKIs.
AB - Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti-cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first-, second-, and third-generation drugs. To explore alternatives to such whack-a-mole strategies, we simulated in patient-derived xenograft models the situation of patients receiving first-line TKIs. Monotherapies comprising approved first-line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance-conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next-generation TKIs.
KW - EGFR TKIs
KW - first-line therapy
KW - mAbs
KW - NSCLC
KW - resistance
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U2 - 10.15252/emmm.202013144
DO - 10.15252/emmm.202013144
M3 - Article
C2 - 33660397
AN - SCOPUS:85101908256
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e13144
ER -