Abstract
Heat Shock Protein 90 inhibitors (HSP90i) have shown activity in EML4-ALK+ non-small cell lung cancer (NSCLC) patients but clinical responses have been heterogeneous. It has been suggested that distinct EML4-ALK variants may have a differential impact on the response to HSP90 inhibition. Here, we show that NSCLC cells harboring the most common EML4-ALK variant 1 (v1) or variant 3 (v3) are in fact similarly sensitive to HSP90i. To discover new genetic alterations that could be involved in stratifying sensitivity, we performed a genome-wide CRISPR/Cas9 knockout screen and found that loss of Spindly increases the sensitivity of EML4-ALK v3, but not v1, NSCLC cells to low concentrations of HSP90i from three distinct chemical families. Upon loss of Spindly, prolonged exposure to low concentrations of HSP90i impairs chromosome congression and cellular fitness. Collectively, our data suggest that mutations leading to loss of Spindly in EML4-ALK v3 NSCLC patients may increase sensitivity to low doses of HSP90i.
Competing Interest Statement
M. P. Licciardello, C. Zhang, P. A. Clarke and P. Workman are current or past employees of The Institute of Cancer Research, which has a commercial interest in the discovery and development of HSP90 inhibitors and operates a reward to inventors scheme. P. Workman is an independent Board Director at Storm Therapeutics, is a consultant/advisory board member at Storm Therapeutics, Astex Pharmaceuticals, CV6 Therapeutics, Black Diamond Therapeutics, Vividion Therapeutics, Alterome Therapeutics and Nextechinvest; reports receiving a commercial research grant from Sixth Element Capital, Astex Pharmaceuticals, and Merck KGaA; has ownership interest in Storm Therapeutics, Chroma Therapeutics, and Nextechinvest; and is an Executive Director of the Chemical Probes Portal. P. Workman has also received relevant research funding from Vernalis, Astex Pharmaceuticals and Nuvectis Pharma. R. C. Doebele is now an employee of Rain Therapeutics. No potential conflicts of interest were disclosed by the other authors.