Determining mechanisms of sensitivity and resistance to HSP90 inhibition in non-small cell lung cancer
thesisposted on 04.10.2016, 09:17 by Edward William Preston Law
BACKGROUND: HSP90 is a molecular chaperone which supports the maturation of numerous client proteins, many of which are involved in oncogenic signaling pathways such as PI3K/AKT, MAPK and JAK/STAT. HSP90 is an appealing target for small molecule inhibitors due to its ability to simultaneously downregulate multiple oncogenic conduits. Results in the clinic have been mixed and biomarkers of response to HSP90 inhibitors for patient stratification remain obscure. RESULTS: 1. EML4-ALK is a HSP90 client which degrades in response to HSP90 inhibition. Variants of EML4-ALK exist with disparate structures and stabilities. This chapter demonstrates differential stability of EML4-ALK variants and cell line sensitivity in response to HSP90 inhibition. A RT-PCR test to identify variants from FFPE tumour tissue is developed for tissues from the CHIARA trial to link variant status and response to ganetespib. 2. Characterisation of a cell line resistant to ganetespib, and verification that high UGT1A levels prevent ganetespib from inhibiting HSP90 in a NSCLC context. 3. Array-based analysis of genome-wide copy number alterations in the GALAXY-1 trial, which examined ganetespib plus docetaxel (G-D) in the second line setting against docetaxel alone (D), following platinum-based chemotherapy in NSCLC patients. Three CNAs were associated with sensitivity to ganetespib plus docetaxel: loss in cytoband 18q23, and gains in 11q13.3 and 16q22.3. Patients with multiple CNAs may represent a group of patients who perform badly on docetaxel but respond much better with the addition of ganetespib. SUMMARY: Several putative biomarkers which are predictive of response to ganetespib are identified in this study. The relationship between EML4-ALK variant stability and ganetespib response may shed light on HSP90 client selection. Genome wide CNA analysis associated with randomized clinical trial survival data has identified putative biomarkers of efficacy to ganetespib plus docetaxel.