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Gastrointestinal stromal tumor (GIST) is the most common GI sarcoma and is generally initiated by KIT or PDGFRA mutations which are compelling therapeutic targets for tyrosine kinase inhibitors (TKI). However, the emergence of secondary mutations results in clinical resistance to available TKIs. GIST progression is driven by genomic events which incrementally target the p16-CDK4/6-RB1 and p14-TP53-RB1 pathways to create CDK4/6 and CDK2 oncogenic co-dependency. Based on limited efficacy of single-agent CDK4/6-inhibitor (CDK4/6i) therapy in GIST, we evaluated strategies of co-targeting CDK2 and CDK4/6. Multiplexed protein imaging (via Immuno-SABER) was validated for the detection of cell cycle regulator aberrations in GIST clinical samples (N=18), 7 of which were TKI-resistant, and including 3 patients in whom multiple metastases were analyzed. The impact of various CDK perturbants using CDK2i (CDK2 inhibitor-II), CDK4/6i (palbociclib or abemaciclib), and CDK2/4/6i (PF-06873600) was determined through cell proliferation and protein detection assays in GIST cell lines and murine xenografts. Mechanisms of acquired CDK2i and CDK4/6i resistance were characterized in GIST cell lines after long-term exposure. Abnormal expression/biallelic inactivation of CDKN2A/p16, RB1, and TP53 were identified in 7 (39%), 2 (11%), and 2 (11%) of 18 GISTs, respectively. Identical aberrations of p16, RB1, and TP53 were present in all metastases from 3 patients. Since 5 of 7 RB1-intact advanced GISTs had co-dysregulation of the CDK2 and CDK4/6 pathways, we evaluated co-inhibition of CDK2 and CDK4/6 in vitro and in vivo which inhibited cell proliferation (P Citation Format: Inga-Marie Schaefer, Meijun Z. Lundberg, Matthew L. Hemming, Sinem K. Saka, Matthew P. Serrata, Isabel Goldaracena, Ninning Liu, Peng Yin, Joao A. Paulo, Steven Gygi, George D. Demetri, Ewa Sicinska, Adrian Mariño-Enríquez, Jason L. Hornick, Chandrajit P. Raut, Wen-Bin Ou, Jonathan A. Fletcher. Response and resistance to CDK2 and CDK4/6 inhibition in GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5648. |
