Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

Neel, Dana S.; Allegakoen, David V.; Olivas, Victor; Mayekar, Manasi K.; Hemmati, Golzar; Chatterjee, Nilanjana; Blakely, Collin M.; McCoach, Caroline E.; Rotow, Julia; Le, Anh‐Tuan; Karachaliou, Niki; Rosell, Rafael; Riess, Jonathan W.; Nichols, R. Jeremy; Doebele, Robert C.; Bivona, Trever G.

doi:10.1158/0008-5472.can-18-1492

Cited by 64 publications

(51 citation statements)

References 49 publications

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“…The data are consistent with SHP2/MEK/ERK activation being the principal effector of FGFR in normal physiology (38) and with the frequent presence of concurrent PIK3CA activating mutations with FGFR2 fusions in ICC, indicating the potential independence of these pathways (14). Although our studies suggested that FGFR2 fusions with different partners had comparable outputs, further studies will be required to fully address the potential differential impact of N-terminus partners on oncoprotein localization, inhibitor sensitivity, and downstream signaling targets, as reported for fusions involving the ROS1 receptor tyrosine kinase (39).…”

Section: Discussionmentioning

confidence: 62%

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

et al. 2019

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ATP-competitive fi broblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated effi cacy in 4 patients with FGFR 2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profi les observed clinically for each inhibitor. Our fi ndings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefi t from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show effi cacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefi t in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.

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Section: Discussionmentioning

confidence: 62%

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

et al. 2019

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“…Neel et al. [50] recently reported that clinically relevant ROS1 RTK fusion oncoproteins show differential subcellular localizations, which impart distinct cell signaling and oncogenic properties. When ROS1 fusion proteins are localized to endosomes, the strongest activations of MAPK signaling are observed.…”

Section: Subcellular Localization Of Receptor Tyrosine Kinases May Gementioning

confidence: 99%

Mutations of FLT3 receptor affect its surface glycosylation, intracellular localization, and downstream signaling

Takahashi

2020

Leukemia Research Reports

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This review describes the effects of FLT3 mutations that alter its intracellular localization and modify its glycosylation, leading to differences in downstream signaling pathways. The most common type of FLT3 mutation, internal tandem duplication (FLT3-ITD), leads to localization in the endoplasmic reticulum and constitutive strong activation of STAT5. In contrast, the ligand-activated FLT3-wild type is mainly expressed on the cell surface and activates MAP kinases. Based on these backgrounds, several reports have demonstrated that glycosylation inhibitors are effective for inhibition of FLT3-ITD expression and intracellular localization. The general subcellular localization regulatory mechanisms for receptor tyrosine kinases are also discussed.

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“…Similarly, the endosome-localized fusion proteins SDC4-ROS1 and SLC34A2-ROS1 and endoplasmic reticulum-localized fusion protein CD74-ROS1 differentially activate mitogen-activated protein kinase (MAPK) (Neel et al, 2019). A study has shown that ROS1 localizes to the cytoplasm in majority of OSCCs, whereas it localizes predominantly to the nucleus in adjacent dysplastic epithelial tissues (Cheng et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ROS1 increases mitochondrial fission and respiration in oral squamous cancer carcinoma

Chang

Chen

2020

Preprint

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Symbols and Abbreviations: COXII, cytochrome c oxidase subunit II; DRP1, dynamin-related protein 1; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; Icorr, index of correlation; MFN2, mitofusin 2; nMDP, normalized mean deviation product; OCR, oxygen consumption rate; OSCC, oral squamous cell carcinoma; OXPHOS, oxidative phosphorylation; P, positively charged residues; RTK, receptor tyrosine kinase; T, transmembrane domain; TP, transmembrane domain with flanking positively charged residues. Summary StatementThis study discovers a new role for the ROS1 in mitochondrial fission and metabolic activities.3 ABSTRACT Increased ROS1 oncogene expression has been implicated in the invasiveness of human oral squamous cell carcinoma (OSCC). The cellular distribution of ROS1 has long been assumed at the plasma membrane.However, a previous work reported a differential cellular distribution of mutant ROS1 derived from chromosomal translocation, resulting in increased carcinogenesis. We thus hypothesized that cellular distribution of up-regulated ROS1 in OSCC may correlate with invasiveness. We found that ROS1 can localize to mitochondria in the highly invasive OSCC and identified a mitochondria-targeting signal sequence in ROS1. We also demonstrated that ROS1 targeting to mitochondria is required for mitochondrial fission phenotype in the highly invasive OSCC cells. OSCC cells expressing high levels of ROS1 consumed more oxygen and had increased levels of cellular ATP levels. Our results also revealed that ROS1 regulates mitochondrial biogenesis and cellular metabolic plasticity. Together, these findings demonstrate that ROS1 targeting to mitochondria enhances OSCC invasion through regulating mitochondrial morphogenesis and cellular respiratory. Acquaviva, J., Wong, R. & Charest, A. (2009). The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Raben, D., Jassem, J., et al. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med, 354, 567-578.

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Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

Cited by 64 publications

References 49 publications

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

Mutations of FLT3 receptor affect its surface glycosylation, intracellular localization, and downstream signaling

Mitochondrial ROS1 increases mitochondrial fission and respiration in oral squamous cancer carcinoma

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