Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas

Abstract

The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas.

HSP90 Inhibition Drives Degradation of FGFR2 Fusion Proteins: Implications for Treatment of Cholangiocarcinoma

“…(10) Within this conceptual framework, attention has recently been drawn to combined targeting of oncogenic kinases through HSP90 inhibition and catalytic blockade, a two-hit strategy aimed at integrating the functional inhibition of the target kinase with its proteolytic destruction. (11) Herein, we report that three FFs, previously identified in ICC, are HSP90 clients and as such undergo rapid degradation in cells subjected to HSP90 inhibition. Furthermore, we show that FF targeting by BGJ398 in combination with the clinically advanced HSP90 inhibitor ganetespib (12) elicits superior suppression of FF oncogenic signaling in cultured cells and FF-driven NIH3T3 tumor allografts.…”

“…This notion has provided the rationale underpinning the use of pharmacological inhibitors of HSP90 (HSP90i) for therapeutic targeting of oncogenic kinases . Within this conceptual framework, attention has recently been drawn to combined targeting of oncogenic kinases through HSP90 inhibition and catalytic blockade, a two‐hit strategy aimed at integrating the functional inhibition of the target kinase with its proteolytic destruction …”

Kajian Heat Shock Protein 90 (HSP90) dalam Pencarian Kandidat Penghambatnya melalui Ekplorasi Bahan Alam Indonesia

“…Pada sel kanker paru-paru, HSP90 berperan dalam stabilisasi protein kinase seperti reseptor EFG, BRAF, HER2, dan ALK (Sang et al, 2013). Gambar 5 menunjukkan bagaimana HSP90 dapat membantu pertumbuhan sel kanker dengan beberapa cara seperti Signifikansi peranan HSP90 dalam pelipatan protein dan stabilisasinya menjadi penelaahan banyak penelitian pada tahun-tahun belakangan ini (Prince et al, 2015). Apalagi peranan HSP90 hampir mendominasi diseluruh tipe protein regulator (Hong et al, 2013).…”

HSP90 as a novel molecular target in non-small-cell lung cancer

“…Recent insights from the Cancer Genome Atlas revealed that multiple malignancies overexpress or possess mutant kinases that depend on the HSP90–chaperone complex. 5 HSP90 has been shown to stabilize various signaling molecules, such as PI3K and AKT proteins, thus inhibiting cellular apoptosis in cancerous cells ( Figure 1 ). 6 It also appears that HSP90 can act as a “protector” of unstable protein by-products of DNA mutations, such as v-SRC and mutant forms of p53.…”