Heat shock protein 90 (HSP90) and client oncogenic kinases (KIT, PDGFRA, BCR-ABL) (HSP90-KIT-PDGFRA-BCR-ABL)

Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone that is critical for the folding, stability, and functional maturation of a wide array of client proteins, many of which are key signaling molecules in oncogenesis [1]. Among its most significant clients are the receptor tyrosine kinases KIT (CD117) and Platelet-derived growth factor receptor alpha (PDGFRA), as well as the non-receptor tyrosine kinase BCR-ABL fusion protein [2, 3]. In malignancies like gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML), these kinases are often mutated or constitutively active, driving uncontrolled cell proliferation and survival [2, 3]. HSP90 inhibitors, such as pimitespib and tanespimycin, disrupt the chaperone cycle by binding to the N-terminal ATP-binding domain of HSP90, which leads to the misfolding and subsequent proteasomal degradation of these client kinases [4]. This multi-targeted approach is particularly effective for overcoming resistance to direct kinase inhibitors, as it results in the total depletion of the oncogenic drivers rather than just blocking their activity [1, 2]. Despite their therapeutic potential, the clinical development of HSP90 inhibitors has faced challenges due to side effects like ocular toxicity and hepatotoxicity [4].

Other names

HSP90-client protein complexHSP90-kinase axisHSP90/KIT/PDGFRA/BCR-ABL pathway

HSP90 inhibitors bind to the N-terminal ATP-binding pocket of the HSP90 chaperone, preventing the maturation and stabilization of client proteins KIT, PDGFRA, and BCR-ABL, which leads to their ubiquitination and subsequent degradation via the 26S proteasome [1, 2, 3].