Dissecting mechanisms and consequences of oncogenic RTK fusion signaling
type: CreativeWork
description: Receptor tyrosine kinase (RTK) fusions are a large class of oncoproteins found in ~5% of cancers. Despite development of targeted therapies for cancers driven by fusion oncogenes, drug resistance remains a significant challenge, in part because we still lack a clear understanding of the broader implications of their activity for cell signaling and how these largely cytoplasmic proteins activate downstream pathways that originate at the plasma membrane. Here, we use optogenetics and live-cell imaging to find that EML4-ALK, an oncogenic fusion present in 5-7% of non-small cell lung cancers, suppress transmembrane RTK signaling by sequestering RTK adapter proteins including GRB2 and SOS1. Furthermore, ALK inhibition, while suppressing oncogenic signaling, simultaneously releases sequestered adapters and thereby resensitizes RTK signaling. Resensitized RTKs promote rapid and pulsatile ERK reactivation originating from paracrine ligands shed by dying cells. Reactivated ERK signaling promotes cell survival, which can be counteracted by combination therapies that block paracrine signaling. EML4-ALK activity is thought to stem from formation of cytoplasmic protein condensates, that result from networks of interactions between oncogene and adapter protein multimers. However, the causal role of condensates in fusion signaling has been challenging to establish and remains unclear. Through single-cell analysis and synthetic fusions we also determine principles by which multimerization drives signaling from cytoplasmic RTK fusions. For EML4-ALK, we found poor correlation between condensation and signaling. By contrast, EML4-ALK activity was abundant in the diffuse phase, and the kinetics of diffuse-phase activity aligned more closely with downstream Erk signaling than did kinetics of signaling within condensates. Synthetic RTK fusions showed cytoplasmic ALK or RET fusion dimers—and even constitutively active monomers—were sufficient to induce strong Ras-Erk signaling despite abs…
abstract: Receptor tyrosine kinase (RTK) fusions are a large class of oncoproteins found in ~5% of cancers. Despite development of targeted therapies for cancers driven by fusion oncogenes, drug resistance remains a significant challenge, in part because we still lack a clear understanding of the broader implications of their activity for cell signaling and how these largely cytoplasmic proteins activate downstream pathways that originate at the plasma membrane. Here, we use optogenetics and live-cell imaging to find that EML4-ALK, an oncogenic fusion present in 5-7% of non-small cell lung cancers, suppress transmembrane RTK signaling by sequestering RTK adapter proteins including GRB2 and SOS1. Furthermore, ALK inhibition, while suppressing oncogenic signaling, simultaneously releases sequestered adapters and thereby resensitizes RTK signaling. Resensitized RTKs promote rapid and pulsatile ERK reactivation originating from paracrine ligands shed by dying cells. Reactivated ERK signaling promotes cell survival, which can be counteracted by combination therapies that block paracrine signaling. EML4-ALK activity is thought to stem from formation of cytoplasmic protein condensates, that result from networks of interactions between oncogene and adapter protein multimers. However, the causal role of condensates in fusion signaling has been challenging to establish and remains unclear. Through single-cell analysis and synthetic fusions we also determine principles by which multimerization drives signaling from cytoplasmic RTK fusions. For EML4-ALK, we found poor correlation between condensation and signaling. By contrast, EML4-ALK activity was abundant in the diffuse phase, and the kinetics of diffuse-phase activity aligned more closely with downstream Erk signaling than did kinetics of signaling within condensates. Synthetic RTK fusions showed cytoplasmic ALK or RET fusion dimers—and even constitutively active monomers—were sufficient to induce strong Ras-Erk signaling despite abs…
author: Gonzalez Martinez, David , Alejandro
language: en
keywords: Engineering, Biology
date published: 2026
date modified: 2026-07-24T03:45:26Z
provider: University of Pennsylvania
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Pennsylvania