Assessing the PI3K pathway in breast cancer: How best to stratify patients
- Carlos Caldas, Cambridge, Cambridgeshire, United Kingdom, Cancer Research UK & University of Cambridge UK
Direct and indirect anti-cancer effects of PI3K isoforms’
- Bart Vanhaesebroeck, London, United Kingdom, UCL - University College London
Targeting the PI3K pathway: Trials and tribulations
- Lori Friedman, South San Francisco, United States of America, Genentech, Inc.
Predictive markers of PIK3CA efficacy
- Fabrice André, Villejuif, France, Gustave Roussy - Cancer Campus
8O - Targeting EGFR exon 20 insertions in non-small cell lung cancer by exploiting a dependency on parallel SRC signalling
- Simon Vyse, London, United Kingdom, The Institute of Cancer Research
Abstract
Background
Inframe insertions in exon 20 of the epidermal growth factor receptor (EGFR) gene are oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike more common EGFR mutations, low frequency EGFR exon 20 insertions are resistant to clinically approved EGFR inhibitors and are associated with poor patient prognosis. There is an unmet clinical need to identify novel therapies that will be effective for patients with EGFR exon 20 insertions.
Methods
Cell viability of three patient-derived NSCLC cell line models harbouring EGFR exon 20 insertions, CUTO14 (A767_V769dupASV), CUTO17 (N771_H773dupNPH) and CUTO18 (S768_D770dupSVD) was assessed after treatment with a chemical compound screen targeting cancer-associated pathways. Western blotting was used to probe cell signalling following dasatinib treatment. Mutant SRC expression constructs were introduced into cell lines via lentiviral transduction and depletion of endogenous SRC levels was achieved using RNAi. Models of acquired drug resistance were developed by long-term drug exposure.
Results
Out of 58 screened compounds, the tyrosine kinase inhibitor dasatinib was a shared hit across all EGFR exon 20 insertion models and was superior to the EGFR inhibitor gefitinib in cell viability and apoptosis assays. Dasatinib sensitivity was rescued by expression of a gatekeeper mutant SRC that does not bind dasatinib, whilst all models were sensitive to RNAi-mediated depletion of endogenous SRC expression. Importantly, models of acquired dasatinib resistance maintain sensitivity to poziotinib, an EGFR inhibitor that can target EGFR exon 20 insertions. Similarly, dasatinib effectively inhibits cell viability of a model of acquired resistance to poziotinib, indicating two independent, targetable signalling nodes. Combined treatment with dasatinib and poziotinib prevented the emergence of drug resistance.
Conclusions
EGFR exon 20 insertion lung cancer models are sensitive to inhibition of parallel SRC signalling via dasatinib treatment. In a patient population with limited therapeutic options, an upfront rational combination of dasatinib with EGFR inhibitors that target EGFR exon 20 insertions has the potential to achieve durable responses.
Legal entity responsible for the study
Paul Huang.
Funding
Institute of Cancer Research, Cancer Research UK.
Disclosure
R. Doebele: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: Genentech/Roche; Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: Ignyta; Licensing / Royalties: Foundation Medicine; Advisory / Consultancy, Licensing / Royalties: Loxo Oncology; Advisory / Consultancy: Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: Rain Therapeutics; Honoraria (self), Advisory / Consultancy: Takeda/Millenium; Licensing / Royalties: Abbot Molecular. All other authors have declared no conflicts of interest.