Loss of Integrin-linked kinase sensitizes breast cancer to SRC inhibitors

Henry Beetham*, Billie Griffith, Olga Murina, Alex Loftus, David A. Parry, Carolin Temps, Jayne Culley, Morwenna Muir, Asier Unciti-Broceta, Andrew H Sims, Adam Byron, Valerie G Brunton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

SRC is a non-receptor tyrosine kinase with key roles in breast cancer development and progression. Despite this, SRC tyrosine kinase inhibitors have so far failed to live up to their promise in clinical trials, with poor overall response rates. We aimed to identify possible synergistic gene-drug
interactions to discover new rational combination therapies for SRC inhibitors. An unbiased genomewide CRISPR-Cas9 knockout screen in a model of triple-negative breast cancer revealed that loss of Integrin-linked kinase (ILK) and its binding partners α-Parvin and PINCH-1 sensitizes cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. Sensitivity to bosutinib did not correlate
with ABL dependency; instead, bosutinib likely induces these effects by acting as a SRC tyrosine kinase inhibitor. Furthermore, in vitro and in vivo models showed that loss of ILK enhanced sensitivity to eCF506, a novel and highly selective inhibitor of SRC with a unique mode of action. Whole-genome RNA sequencing following bosutinib treatment in ILK knockout cells identified broad changes in the expression of genes regulating cell adhesion and cell-extracellular matrix.
Increased sensitivity to SRC inhibition in ILK knockout cells was associated with defective adhesion, resulting in reduced cell number as well as increased G1 arrest and apoptosis. These findings support the potential of ILK loss as an exploitable therapeutic vulnerability in breast cancer, enhancing the effectiveness of clinical SRC inhibitors.
Statement of Significance
A CRISPR-Cas9 screen reveals that loss of integrin-linked kinase synergizes with SRC inhibition, providing a new opportunity for enhancing the clinical effectiveness of SRC inhibitors in breast cancer.
Original languageEnglish
JournalCancer Research
Early online date17 Dec 2021
DOIs
Publication statusE-pub ahead of print - 17 Dec 2021

Keywords

  • Breast cancer
  • synthetic lethality
  • bosutinib
  • Integrin-linked kinase
  • SRC

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