Abstract LB-88: Identification of recurrent oncogenic KIF5B-RET rearrangements in non-small cell lung cancer
Authors: Capelletti Marzia , Lipson Doron , Otto Geoff , Yelensky Roman , Ercan Dalia , Kim Jhingook Kim , Sasaki Hidefumi , Kim Hyeong Ryul , Park Seung-il , Ross Jeffrey , Stephens Philip J. , Cronin Maureen T. , Jänne Pasi A. 
Published: August 2012

Abstract
Background: A large number of non-small cell lung cancer (NSCLC) cases from never/former light smokers can be explained by driving oncogenic alterations in EGFR, KRAS, ERBB2, BRAF, ALK and ROS1. EGFR and ALK targeted tyrosine kinase inhibitors are effective clinical therapies for EGFR mutant and ALK rearranged NSCLC, respectively. We wished to study cancers that do not harbor a known genomic alteration in order to identify novel therapeutic targets that may increase treatment options for NSCLC patients. Methods and Results: We initially sequenced a NSCLC specimen from a 44 year old Caucasian never smoker in a CLIA certified lab (Foundation Medicine) using a next generation sequencing assay that captures and sequences 2574 coding exons representing 145 cancer relevant genes plus 37 introns from 14 genes frequently rearranged in cancer. We identified an 11,294,741 bp pericentric inversion on chromosome 10 generating a novel gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET (K15:R12). This fusion gene contains the kinesin motor and coiled-coil domains of KIF5B and the entire tyrosine kinase domain of RET. Expression of RET was confirmed by immunohistochemistry (IHC) and cDNA sequencing detected a 7.3-fold RET expression increase beginning at exon 12 relative to exons 1-11. Screening of additional 117 NSCLC patients using RET IHC identified 22 positive cases; sequencing of 15/22 of these identified 1 additional patient with a KIF5B-RET fusion. We also evaluated 526 tumors from never/former limited smokers (121 Caucasian and 405 Asian) and identified 10 additional (1/121 Caucasian (0.8%) and 9/405 Asian (2%)) positive patients. All fusion positive tumors were wild type for known oncogenes (frequency of 6.3 % (10/159) in WT patients). Four unique KIF5B-RET variants were identified: 8 K15:R12 (variant 1), 3 K16:R12 (variant 2), 1 K22:R12 (variant 3) and 1 K15:R11 (variant 4). We introduced K15:R12 (variant 1) into Ba/F3 cells and observed IL-3 independent growth consistent with oncogenic transformation. These KIF5B-RET Ba/F3 cells were sensitive to sunitinib, sorafenib and vandetinib, multi-targeted kinase inhibitors that inhibit RET, but not gefitinib, an EGFR kinase inhibitor. Sunitinib, but not gefitinib, inhibited RET phosphorylation in the KIF5B-RET Ba/F3 cells. Conclusions: We identify a novel oncogenic KIF5B-RET fusion gene in a subset of NSCLC patients lacking other known driver mutations. Our findings suggest that RET kinase inhibitors should be tested in prospective clinical trials for therapeutic benefit in NSCLC patients bearing KIF5B-RET rearrangements.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-88. doi:1538-7445.AM2012-LB-88