Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance

David Gonzalez-Martinez, Lee Roth, Thomas R. Mumford, Juan Guan, Anh Le, Robert C. Doebele, Bo Huang, Asmin Tulpule, Magdalena Niewiadomska-Bugaj, Trever G. Bivona and Lukasz J. Bugaj ()
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David Gonzalez-Martinez: University of Pennsylvania
Lee Roth: University of Pennsylvania
Thomas R. Mumford: University of Pennsylvania
Juan Guan: University of Florida
Anh Le: University of Colorado School of Medicine
Robert C. Doebele: University of Colorado School of Medicine
Bo Huang: UCSF
Asmin Tulpule: Memorial Sloan Kettering Cancer Center
Magdalena Niewiadomska-Bugaj: Western Michigan University
Trever G. Bivona: UCSF
Lukasz J. Bugaj: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53451-7

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