Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance Journal Article
| Authors: | Gonzalez-Martinez, D.; Roth, L.; Mumford, T. R.; Guan, J.; Le, A.; Doebele, R. C.; Huang, B.; Tulpule, A.; Niewiadomska-Bugaj, M.; Bivona, T. G.; Bugaj, L. J. |
| Article Title: | Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance |
| Abstract: | Drug resistance remains a challenge for targeted therapy of cancers driven by EML4-ALK and related fusion oncogenes. EML4-ALK forms cytoplasmic protein condensates, which result from networks of interactions between oncogene and adapter protein multimers. While these assemblies are associated with oncogenic signaling, their role in drug response is unclear. Here, we use optogenetics and live-cell imaging to find that EML4-ALK assemblies suppress transmembrane receptor tyrosine kinase (RTK) signaling by sequestering RTK adapter proteins including GRB2 and SOS1. Furthermore, ALK inhibition, while suppressing oncogenic signaling, simultaneously releases the sequestered adapters and thereby resensitizes RTK signaling. Resensitized RTKs promote rapid and pulsatile ERK reactivation that originates from paracrine ligands shed by dying cells. Reactivated ERK signaling promotes cell survival, which can be counteracted by combination therapies that block paracrine signaling. Our results identify a regulatory role for RTK fusion assemblies and uncover a mechanism of tolerance to targeted therapies. © The Author(s) 2024. |
| Keywords: | signal transduction; intercellular signaling peptides and proteins; genetics; mouse; animal; metabolism; animals; mice; drug effect; drug resistance; drug resistance, neoplasm; cell line, tumor; protein tyrosine kinase; signal peptide; tumor cell line; oncogene proteins, fusion; receptor protein-tyrosine kinases; perception; grb2 adaptor protein; growth factor receptor bound protein 2; cell; reactivation; humans; human; optogenetics; growth response; oncogene fusion protein; eml4-alk fusion protein, human |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-11-02 |
| Start Page: | 9473 |
| Language: | English |
| DOI: | 10.1038/s41467-024-53451-7 |
| PUBMED: | 39488530 |
| PROVIDER: | scopus |
| PMCID: | PMC11531495 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
