Inhibition of Casein Kinase 1 Alpha Prevents Acquired Drug Resistance to Erlotinib in EGFR-Mutant Non-Small Cell Lung Cancer.
Patients with lung tumors harboring activating mutations in the EGF receptor (EGFR) show good initial treatment responses to the EGFR tyrosine kinase inhibitors (TKI) erlotinib or gefitinib. However, acquired resistance invariably develops. Applying a focused shRNA screening approach to identify genes whose knockdown can prevent and/or overcome acquired resistance to erlotinib in several EGFR-mutant non-small cell lung cancer (NSCLC) cell lines, we identified casein kinase 1 α (CSNK1A1, CK1α). We found that CK1α suppression inhibits the NF-κB prosurvival signaling pathway. Furthermore, downregulation of NF-κB signaling by approaches independent of CK1α knockdown can also attenuate acquired erlotinib resistance, supporting a role for activated NF-κB signaling in conferring acquired drug resistance. Importantly, CK1α suppression prevented erlotinib resistance in an HCC827 xenograft model in vivo. Our findings suggest that patients with EGFR-mutant NSCLC might benefit from a combination of EGFR TKIs and CK1α inhibition to prevent acquired drug resistance and to prolong disease-free survival.
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. sreenathsharma@hotmail.com alexandra.lantermann@novartis.com.
Alexandra B
AB
Lantermann
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Dongshu
D
Chen
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Kaitlin
K
McCutcheon
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Greg
G
Hoffman
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Elizabeth
E
Frias
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
David
D
Ruddy
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Daniel
D
Rakiec
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Joshua
J
Korn
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Gregory
G
McAllister
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Frank
F
Stegmeier
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Matthew J
MJ
Meyer
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. sreenathsharma@hotmail.com alexandra.lantermann@novartis.com.
Sreenath V
SV
Sharma
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics*; D047389:Casein Kinase I / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D018773:Genes, erbB-1 / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D000069347:Erlotinib Hydrochloride; D047389:Casein Kinase I