Abstract 2642: Evaluation of the mechanism of MET-dependent cellular transformation and potent cytoreductive activity of MGCD265 in novel MET exon 14 mutation positive cancer models
Authors: Engstrom Lars D. , Tang Ruth W. , Briere David M. , Chiang Harrah , Olson Peter , Christensen James G. 
Published: July 2016

MET splice site mutations that result in the deletion of exon 14 (METex14del) are implicated as oncogenic drivers in a subset of non-small cell lung cancer (NSCLC). MET exon 14 contains the Y1003 CBL ubiquitin ligase regulatory binding site that normally mediates CBL-dependent MET degradation and signal attenuation. Deletion of this exon results in sustained activation of MET and its downstream signaling pathways. The diverse splice site mutations leading to exon 14 skipping comprise a unique and unprecedented class of RTK activating mutations and the molecular mechanism by which these genetic alterations transform cancer cells is not fully understood. One major challenge in understanding the utility of MET inhibition of the METex14del class has been the lack of available pre-clinical models.

In the present study, we generated and characterized multiple METex14del-driven cancer models to study the mechanism of MET-dependent cellular transformation as well as the response to MGCD265, a small molecule inhibitor of MET and AXL. METex14del models were identified via mining patient-derived xenograft (PDX) databases or were engineered using genome editing techniques to generate isogenic pairs of METex14del and WT cell lines.

The METex14del cell lines formed increased size and number of colonies in anchorage independent growth assays compared to their WT counterparts. The transformation of METex14del cells was associated with an increase in durable HGF-dependent activation of MET and downstream signaling pathways potentially due to dysregulated MET processing and signaling attenuation. MGCD265 was shown to effectively inhibit this growth and MET-dependent signal transduction in a concentration-dependent manner. When evaluated in the amplified METex14del-driven gastric xenograft model Hs746T, significant tumor regression was observed following MGCD265 treatment. In addition, MGCD265 demonstrated substantial regression of large established tumors, in two novel NSCLC METex14del-positive PDX models.

Together, these data confirm METex14del mutations are bona fide oncogenic drivers and sensitive to targeted therapeutics. Moreover, the models described in this study represent a relevant pre-clinical platform to further study receptor hyper-activation and drug action that is clinically actionable. Identification, development, and understanding of METex14del models will likely help further guide precision medicine strategies to treat NSCLC patients harboring these mutations.

Citation Format: Lars D. Engstrom, Ruth W. Tang, David M. Briere, Harrah Chiang, Peter Olson, James G. Christensen. Evaluation of the mechanism of MET-dependent cellular transformation and potent cytoreductive activity of MGCD265 in novel MET exon 14 mutation positive cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2642.