TY - JOUR
T1 - A combination of approved antibodies overcomes resistance of lung cancer to osimertinib by blocking bypass pathways
AU - Romaniello, Donatella
AU - Mazzeo, Luigi
AU - Mancini, Maicol
AU - Marrocco, Ilaria
AU - Noronha, Ashish
AU - Kreitman, Matthew
AU - Srivastava, Swati
AU - Ghosh, Soma
AU - Lindzen, Moshit
AU - Salame, Tomer Meir
AU - Onn, Amir
AU - Bar, Jair
AU - Yarden, Yosef
PY - 2018
Y1 - 2018
N2 - Purpose: Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and in vitro an alternative therapeutic approach making use of antibodies. Experimental Design: An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed. Results: Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3. Conclusions: Our in vitro assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance.
AB - Purpose: Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and in vitro an alternative therapeutic approach making use of antibodies. Experimental Design: An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed. Results: Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3. Conclusions: Our in vitro assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance.
KW - Drug resistance
KW - EGFR
KW - Lung cancer
KW - Drug resistance
KW - EGFR
KW - Lung cancer
UR - http://hdl.handle.net/10807/227191
U2 - 10.1158/1078-0432.CCR-18-0450
DO - 10.1158/1078-0432.CCR-18-0450
M3 - Article
SN - 1078-0432
VL - 24
SP - 5610
EP - 5621
JO - Clinical Cancer Research
JF - Clinical Cancer Research
ER -