Vesicle Trafficking in Cancer

XIV, 393 p. 50 illus., 47 illus. in color.online

An Unbiased Screen Identifies DEP-1 Tumor Suppressor as a Phosphatase Controlling EGFR Endocytosis

SummaryBackgroundThe epidermal growth factor (EGF) stimulates rapid tyrosine phosphorylation of the EGF receptor (EGFR). This event precedes signaling from both the plasma membrane and from endosomes, and it is essential for recruitment of a ubiquitin ligase, CBL, that sorts activated receptors to endosomes and degradation. Because hyperphosphorylation of EGFR is involved in oncogenic pathways, we performed an unbiased screen of small interfering RNA (siRNA) oligonucleotides targeting all human tyrosine phosphatases.ResultsWe report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex. DEP-1 silencing enhanced tyrosine phosphorylation of endosomal EGFRs and, accordingly, increased cell proliferation. In line with functional interactions, EGFR and DEP-1 form physical associations, and EGFR phosphorylates a substrate-trapping mutant of DEP-1. Interestingly, the interactions of DEP-1 and EGFR are followed by physical segregation: whereas EGFR undergoes endocytosis, DEP-1 remains confined to the cell surface.ConclusionsEGFR and DEP-1 physically interact at the cell surface and maintain bidirectional enzyme-substrate interactions, which are relevant to their respective oncogenic and tumor-suppressive functions. These observations highlight the emerging roles of vesicular trafficking in malignant processes

Revisited analysis of a SHIVA01 trial cohort using functional mutational analyses successfully predicted treatment outcome

It still remains to be demonstrated that using molecular profiling to guide therapy improves patient outcome in oncology. Classification of somatic variants is not straightforward, rendering treatment decisions based on variants with unknown significance (VUS) hard to implement. The oncogenic activity of VUS and mutations identified in 12 patients treated with molecularly targeted agents (MTAs) in the frame of SHIVA01 trial was assessed using Functional Annotation for Cancer Treatment (FACT). MTA response prediction was measured in vitro, blinded to the actual clinical trial results, and survival predictions according to FACT were correlated with the actual PFS of SHIVA01 patients. Patients with positive prediction had a median PFS of 5.8 months versus 1.7 months in patients with negative prediction (P < 0.05). Our results highlight the role of the functional interpretation of molecular profiles to predict MTA response

Abstract CT212: Expanded phase 1/2a study of PLX8394, a novel next generation BRAF inhibitor in patients with advanced, unresectable solid tumors with alterations in BRAF

Abstract The authors did not submit an updated abstract. The original abstract should be considered final. Citation Format: Filip Janku, Eric Sherman, Rona Yaeger, Aparna Parikh, Ryan Sullivan, Lynn Feun, Macarena De La Fuente, Frank Yung-Chin Tsai, Michael Gordon, Carl Allen, Marc S. Rudoltz, Kathe Balinski, Steven Averbuch, Michael Vidne, Gabi Tarcic. Expanded phase 1/2a study of PLX8394, a novel next generation BRAF inhibitor in patients with advanced, unresectable solid tumors with alterations in BRAF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT212