Abstract 2949
Background
The tyrosine kinase inhibitors (TKIs) lapatinib (L), a reversible dual EGFR/HER2 inhibitor, and afatinib (A), an irreversible pan-HER inhibitor, are approved for the treatment of HER2+ BC and EGFR mutant non-small cell lung cancer (NSCLC), respectively. Anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors are showing clinical activity in HER2+ BC and NSCLC. Pre-clinical studies in EGFR-mutant NSCLC models suggest that there may be a link between EGFR activity and PD-L1 expression. This study investigates the potential of the EGF signalling pathway to alter PD-L1 expression in parental and L- or A-resistant HER2+ BC cell lines to examine the pre-clinical rationale for the combination of anti-PD-1/PD-L1 agents and TKIs in HER2+ BC.
Methods
Parental (HCC1954-P, SKBR3-P) and TKI-resistant HER2+ breast cancer cell lines (L-resistant HCC1954-L, A-resistant SKBR3-A) were treated with the EGFR ligand EGF (10ng/ml) alone, L (1µM) alone or the combination of EGF and L for 24 hours. Protein lysates were generated. PD-L1 (CST E1L3N), EGFR (ThermoFisher MS665) and pEGFR y1068 (Millipore 07818) expression levels were assessed by Western blot. Densitometry analysis was carried out on triplicate data using Total Lab Quant. A Student’s t test p value of < 0.05 was considered significant.
Results
All cell lines examined showed a significant increase in PD-L1 expression upon EGF treatment (HCC1954-P – 3-fold increase (p = 0.02), HCC1954-L - 2.5 fold increase (p = 0.03), SKBR3-P - 4.4 fold increase (p = 0.03), SKBR3-A - 1.9 fold increase (p = 0.01)). L was capable of blocking EGF-mediated PD-L1 upregulation in the HCC1954-P, SKBR3-P an SKBR3-A cell lines (p = 0.04, p = 0.04 and p = 0.01 respectively). L was not capable of blocking EGF-mediated PD-L1 upregulation in the HC1954-L cell line. For parental and resistant cell line models, pEGFR levels corresponded to PD-L1 expression upon EGF and L treatment.
Conclusions
The results indicate PD-L1 expression can be altered by manipulation of EGFR activity in HER2+ breast cancer cell line models. The development of targeted therapy resistance can interfere with the ability of EGFR to impact PD-L1 levels. Further examination of EGFR and PD-L1 is warranted in HER2+ breast cancer models.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Cancer Clinical Research Trust.
Disclosure
A. Canonici: Research grant/Funding (institution): Boehringer Ingelheim. J. Crown: Full/Part-time employment: OncoMark; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eisai; Honoraria (self): Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Vertex; Honoraria (self), Speaker Bureau/Expert testimony: Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: MSD Oncology; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Abbvie. D.M. Collins: Research grant/Funding (self): Puma Biotechnology; Research grant/Funding (self): Roche. All other authors have declared no conflicts of interest.
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