Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer.
Basal-like breast cancers (BLBC) are highly aggressive, yet selective therapies targeting the specific oncoproteins driving these tumors have not been developed. These cancers frequently express epidermal growth factor receptor (EGFR), with resistance to its inhibition being well documented, albeit poorly understood. Notch pathway activation is also common in this breast cancer subtype and can be suppressed by gamma-secretase inhibitors, which effectively block receptor cleavage and activation. Herein, we show that although inhibition of either EGFR or Notch signaling alone is insufficient to suppress basal-like breast tumor cell survival and proliferation, simultaneous inhibition uncovers a synthetic lethal relationship between these two oncogenic pathways. This lethality is due in part to significant decreases in AKT activation caused by combined EGFR and Notch inhibition. Expression of the activated form of Notch1 restores AKT activity and enables cells to overcome cell death after dual-pathway blockade. Combined pathway inhibition is also dramatically more effective at suppressing tumor growth in mice than blocking EGFR or Notch signaling alone. Thus, we show that Notch pathway activation contributes to resistance to EGFR inhibition, and provide a novel treatment strategy for BLBCs.
Dong
Yiyu
Y
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Li
Aimin
A
Wang
Jianbo
J
Weber
Jason D
JD
Michel
Loren S
LS
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002470:Cell Survival; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051880:Receptors, Notch; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D000077156:Gefitinib