NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

Abstract

Background/Aim: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusionpositive solid tumors. Patient and Methods: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. Results: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K-and JAK/STAT-pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. Conclusion: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse.The most common solid malignancies of childhood are tumors of the central nervous system (CNS). Glioma comprises the largest group of CNS tumors among these patients (40-50%), 711

CD74–ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non‐small cell lung cancer cells

“…To clarify the mechanism of CD74‐ROS1 L2026M‐induced migration and invasion enhancement in NSCLC cells, we investigated the expression of MEK/ERK, STAT3, and PI3K/AKT signaling pathways by western blot, which are reported to be the downstream of ROS1 [6,23]. Compared with CD74‐ROS1 group, the expression of CD74‐ROS1 L2026M mutant gene in NSCLC cells resulted in the increase of protein levels of p‐MEK, MEK, p‐ERK, and PI3K (Fig.…”

“…western blot, which are reported to be the downstream of ROS1 [6,23]. Compared with CD74-ROS1 group, the expression of CD74-ROS1 L2026M mutant gene in NSCLC cells resulted in the increase of protein levels of p-MEK, MEK, p-ERK, and PI3K (Fig.…”

Advancements in NSCLC

“…Yet, the precise mechanism of ROS1 kinase activation within the fusion proteins remains to be determined. Intriguingly, the localization of ROS1 fusion proteins varies, and upon activation, ROS1 signals through the MAPK/ERK, PI3K/AKT, JAK/STAT3, and SHP1/2 pathways to bolster cell growth and survival 39 . Whether different ROS1 fusions bestow varying expression levels, kinase activations, and oncogenicities is still an open question.…”

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

“…A classic example of transcription factor fusion is the EWSR1::FLI1 fusion, which is a common driver in Ewing sarcoma [79,80]. The most notable protein kinases involved in fusions include the MAST kinases in breast cancer [81], present in 3 to 5% of cases, as well as RET in various cancers (particularly lung and thyroid) [76,[82][83][84] and other RTKs in a variety of tumors [36,36,[85][86][87][88][89][90][91][92][93][94][95][96][97]. Such rearrangements are occasionally cancer-specific, or may be observable in distinctly different cancer types.…”