USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K

Abstract

Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto‐oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl‐terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto‐oncogenes such as c‐JUN, c‐MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed‐forward loop, driven by increased amounts of oncogenic transcription factors such as c‐MYC and c‐JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small‐molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R‐, BRAFV600E‐ or PI3KH1047R‐driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early‐stage lung tumours, and the observed synergism with current standard‐of‐care inhibitors holds the potential for improved targeting of established tumours.

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer

“…Whole cell proteome analysis of A431 cells expressing shRNAs targeting USP28 or non-targeting controls and treated with 1 µg/mL doxycycline for 72 h has been described previously [10,18]. Pathway analysis of USP28 regulated proteins (FDR p-value ≤ 0.05) was performed with the PANTHER tool using the statistical overrepresentation test and PANTHER pathways with default settings [19].…”

“…Furthermore, pharmacologic inhibition of USP28 negatively affected LSCC tumour growth and was well tolerated in vivo [16,17]. In addition, USP28 supports oncogenic transformation of respiratory cells and its inhibition synergises with therapeutic strategies targeting the EGFR/RAS/ERK pathway in transformed lung epithelial cells [18]. Therefore, understanding the molecular mechanisms by which USP28 supports tumour formation is vital for the rational targeting of LSCC.…”