Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. READ ARTICLE

Cell DOI:10.1016/j.cell.2021.03.031

Authors: Asmin Tulpule, Juan Guan, Dana S Neel, Hannah R Allegakoen, Yone Phar Lin, David Brown, Yu-Ting Chou, Ann Heslin, Nilanjana Chatterjee, Shriya Perati, Shruti Menon, Tan A Nguyen, Jayanta Debnath, Alejandro D Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Suraj Makhija, Bo Huang, Trever G Bivona

Pre-ClinicalKirk SmithApril 12, 2021ALK, MAPK, RAS, RET, biomolecular condensate, gene fusion, kinase, protein granule, receptor tyrosine kinase

RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS–mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRASWT) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK–positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes. READ ARTICLE

Nature Medicine DOI:10.1038/nm.3930

Authors: Gorjan Hrustanovic, Victor Olivas, Evangelos, Pazarentzos, Asmin Tulpule, Saurabh Asthana, Collin M. Blakely, Ross A. Okimoto, Luping Lin, Dana S. Neel, Amit Sabnis, Jennifer Flanagan, Elton Chan, Marileila, Varella-Garcia, Dara L. Aisner, Aria Vaishnavi, Sai-Hong I. Ou, Eric A. Collisson, Eiki Ichihara, Philip C. Mack, Christine M. Lovly, Niki Karachaliou, Rafael Rosell, Jonathan W. Riess, Robert C. Doebele & Trever G. Bivona

Pre-ClinicalKirk SmithSeptember 4, 2015lung adenocarcinoma, MAPK, polytherapy