Loss of Integrin-Linked Kinase sensitizes breast cancer to SRC inhibitors
Our researchers demonstrated that loss of Integrin-Linked Kinase sensitizes triple negative breast cancer to SRC inhibition: February 2022
SRC family kinases (SFKs) are enzymes capable of modifying various proteins by phosphorylation of their tyrosine residues. They can also act as “scaffolds”, enabling formation of protein complexes that are important for multiple aspects of cellular behaviour, for example cell proliferation and motility. Abnormalities in SRC signalling have been described in several cancer types including breast, colon and gastric cancers. Additionally, there is considerable evidence that SFKs represent key regulators of tumour development and progression.
Several SRC inhibitors have been developed to date, but they have failed to live up to their promise in clinical trials so far. This indicates that our understanding of SRC biology is still insufficient, and that more work is required before SRC-targeting therapeutics can fully benefit cancer patients.
Researchers from CRUK Edinburgh Centre undertook a project set to identify proteins whose inhibition could synergise with action of SRC inhibitors providing new opportunities for enhancing their clinical effectiveness. Using a model of triple-negative breast cancer (breast cancer type that tests negative for oestrogen receptors, progesterone receptors, and excess HER2 protein), they employed a genome-wide CRISPR-Cas9 knockout approach to show that loss of Integrin-Linked Kinase (ILK; a protein implicated in transduction of signals from extracellular matrix), and its binding partners alpha-Parvin and PINCH-1, sensitizes breast cancer cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. The team, led by Professor Valerie Brunton, also demonstrated that loss of ILK enhances sensitivity to eCF506 (also known as NXP900), a novel and highly selective SRC inhibitor (discovered in Edinburgh and licensed to Nuvectis Pharma, Inc.) that not only blocks SRC kinase activity but also locks the protein in its inactive conformation preventing scaffolding functions. Notably, in their experiments, eCF506 was significantly more potent than bosutinib, supporting the notion that complete shutdown of SRC-mediated signalling (both as kinase and scaffold protein) is key to unlocking the full potential of SRC inhibition as an anti-cancer treatment strategy. Results of the study have been published by the journal Cancer Research in the article titled “Loss of Integrin-Linked Kinase sensitizes breast cancer to SRC inhibitors”. The project was funded by Breast Cancer Now, with additional support from CRUK and MRC.
Our main findings are that loss of ILK sensitizes breast cancer to SRC/YES1 inhibitors and that this exposes a therapeutic vulnerability in breast cancer, representing a potential avenue for clinical development. We are enthusiastic about NXP900's promising activity in in vitro and in vivo models and hope this can pave the way for improved breast cancer treatment in the future.
Article in Cancer Research: https://doi.org/10.1158/0008-5472.CAN-21-0373
Professor Val Brunton Group website: https://www.ed.ac.uk/cancer-centre/research/brunton-group
Information about breast cancer: https://www.cancerresearchuk.org/about-cancer/breast-cancer
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