The conformation-specific Hsp90 inhibition interferes with the oncogenic RAF kinase adaptation and triggers premature cellular senescence, hence, acts as a tumor suppressor mechanism

• Published in: Biochimica et biophysica acta. Molecular cell research 2021-03, Vol.1868 (3), p.118943-118943, Article 118943
• Main Authors: Kanugovi Vijayavittal, Abhijnya, Amere Subbarao, Sreedhar
• Format: Article
• Language: English
• Subjects: Cancer; Hsp90; Kinase; RAF; Senescence
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2020.118943

Cancer emergence is associated with cellular adaptations to altered signal transduction mechanisms arbitrated by mutated kinases. Since conventional kinase inhibitors can exhibit certain limitations to such kinase adaptations, overcoming kinase adaptation for cancer treatment gains importance. The cancer chaperone, Hsp90, is implicated in the conformational maturation and functional stabilization of mutated gene products. However, its role in kinase adaptations is not explored in detail. Therefore, the present study aims to understand the mechanisms of Hsp90-dependent kinase adaptation and develop a novel antitumor strategy. We chose malignant human lung cancer cells to demonstrate Hsp90-dependent RAF oncogene adaptation. We show that RAF oncogene adaptations were predominant over wild type RAF and are facilitated by conformation-specific Hsp90. Consequently, the conformation-specific Hsp90 inhibitor, 17AAG, interfered with oncogenic RAF stability and function and inhibited cell proliferation. The enforced cytostasis further triggered premature cellular senescence and acted as an efficient and irreversible tumor suppressor mechanism. Our results also display that oncogenic RAF interactions with Hsp90 require the middle-charged region of the chaperone. Our mice xenografts revealed that 17AAG pretreated tumor cells lost their ability to proliferate and metastasize in vivo. In summary, we demonstrated Hsp90-dependent kinase adaptation in tumor cells and the effect of Hsp90 inhibition in triggering premature senescence to interfere with the tumor progression. Our findings are of both biological relevance and clinical importance. Cells, after a definite number of divisions, enter into a non-dividing state called senescence. The accumulation of mutations in the proto-oncogenes leads to oncogenic kinase activation. These cells require conformation-specific Hsp90 chaperone for functional stabilization, maturation, and cellular adaptation of such kinases. While oncogenic mutations contribute to cancer progression, their adaptation helps in bypassing the senescence program. Conformation-specific Hsp90 inhibitors disassociate Hsp90-kinase interaction and promote kinase de-adaptation followed by its degradation. Abrupt cell cycle inhibition, therefore, leads to DNA damage response and activate stress-induced premature cellular senescence. Induced premature senescence in tumor cells acts as a tumor suppressor mechanism. [Display omitted] •Mutant kinase overexpression i