A Novel ALK Secondary Mutation and EGFR Signaling Cause Resistance to ALK Kinase Inhibitors

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 18; pp. 6051 - 6060
• Main Authors: SASAKI, Takaaki, KOIVUNEN, Jussi, CAPELLETTI, Marzia, SHIMAMURA, Takeshi, ERCAN, Dalia, STUMPFOVA, Magda, YUN XIAO, WEREMOWICZ, Stanislawa, BUTANEY, Mohit, HEON, Stephanie, WILNER, Keith, CHRISTENSEN, James G, OGINO, Atsuko, ECK, Michel J, WONG, Kwok-Kin, LINDEMAN, Neal, GRAY, Nathanael S, RODIG, Scott J, JÄNNE, Pasi A, YANAGITA, Masahiko, NIKIFOROW, Sarah, ZHENG, Wei, LATHAN, Christopher, PAUL MARCOUX, J, JINYAN DU, OKUDA, Katsuhiro
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2011
• Subjects: Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell survival; Drug resistance; Drug Resistance, Neoplasm; Epidermal growth factor receptors; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical sciences; Models, Molecular; Mutation; Non-small cell lung carcinoma; Oncogene Proteins, Fusion - biosynthesis; Oncogene Proteins, Fusion - genetics; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Pyrazoles - pharmacology; Pyridines - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Tumors; Secondary; Enzyme; Transferases; Epidermal growth factor receptor; Resistance; Signal transduction; Kinase; C-Onc gene; Genetics; Inhibitor; Mutation; Anaplastic lymphoma kinase; Protooncogene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-1340

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.