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Identifying novel molecular vulnerabilities to PTK2/FAK inhibition in G α q‐driven uveal melanoma using a kinome‐wide CRISPR/Cas9 screen
Author(s) -
Kishore Ayush,
Feng Xiaodong,
Arang Nadia,
Wu Xingyu,
Pachter Jonathan,
Schlaepfer David D.,
Tamayo Pablo,
Cheng Qianming,
Gutkind J. Silvio
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.647.15
Subject(s) - kinome , cancer research , focal adhesion , melanoma , selumetinib , ptk2 , neuroblastoma ras viral oncogene homolog , biology , tyrosine kinase , trametinib , medicine , kinase , signal transduction , mapk/erk pathway , microbiology and biotechnology , mek inhibitor , gene , genetics , mutation , protein kinase a , kras , mitogen activated protein kinase kinase
Uveal melanoma (UM) is the most common primary cancer of the eye in adults. It is diagnosed in about 2,500 adults in the United States every year. Approximately 50% of UM patients develop liver metastasis within 5–10 years after diagnosis, independently of successful treatment of the primary lesions. Activating mutations in GNAQ and GNA11 (encoding GTPase deficient/constitutively active Gαq proteins) were identified in ~90% of UM; where they act as driver oncogenes. MEK inhibition with selumetinib or trametinib has nearly no impact on the overall survival of UM patients. Therefore, there is an urgent need to understand mechanistically how Gαq promotes UM progression in order to develop new therapeutics. In a recent study, we have performed an integrated bioinformatics analysis of gene interaction networks and identified PTK2 , encoding the tyrosine kinase: Focal Adhesion Kinase (FAK) as a candidate gene highly predicted to contribute to Gαq‐driven UM progression. Using a variety of biochemical and cell‐based assays, we established that FAK is indeed a pivotal signaling node downstream of oncogenic Gαq that mediates UM proliferation through the activity of the growth‐promoting transcription factor Yap. Notably, our studies with UM xenograft mouse models demonstrated that FAK blockade by VS‐4718, a new generation orally‐bioavailable FAK inhibitor, dramatically reduced tumor volume. The major objective of the current study is to further delineate the Gαq‐FAK signaling axis with interest in identifying novel synthetic lethal interactions to FAK inhibition in UM. To this end, we conducted a kinome‐wide CRISPR/Cas9 screen using VS‐4718 in UM cell line OMM1.5 to pinpoint molecular vulnerabilities in the Gαq‐FAK onco‐circuitry. Positive hits from our gene‐drug screen will be presented, which shed light on the Gαq‐FAK network and may serve as potential co‐targets to FAK inhibition in UM clinical therapy. Support or Funding Information Cancer Biology, Informatics & Omics Training Program This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .