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.
Resources from the same session
1613 - Lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed continuously in combination with osimertinib for EGFRmut non-small cell lung cancer: initial Phase 1b results
Presenter: David Berz
Session: Poster Display session 1
Resources:
Abstract
2853 - Real-world implementation of sequential targeted therapies for EGFR-mutated NSCLC
Presenter: Petros Christopoulos
Session: Poster Display session 1
Resources:
Abstract
1974 - A Phase II Open-Label, Multicentre Study to Assess the Anti-tumour Activity of Afatinib in Patients with Activating Epidermal Growth Factor Receptor mutation (EGFRm) from Circulating Tumor DNA (CtDNA)
Presenter: Young-Chul Kim
Session: Poster Display session 1
Resources:
Abstract
3370 - Influence of cow’s milk on the absorption and exposure of erlotinib in NSCLC patients
Presenter: Geerten Veerman
Session: Poster Display session 1
Resources:
Abstract
5900 - PTEN loss as Predictor of Tumor Heterogeneity (TH) and Poor Prognosis in EGFR-mutant Advanced Non-Small Cell Lung Cancer (ANSCLC) Patients (pts) Receiving Tyrosine-Kinase Inhibitors (TKIs).
Presenter: Miriam Ferrara
Session: Poster Display session 1
Resources:
Abstract
1302 - Safety of lorlatinib in subgroups of patients from a phase 1/2 trial
Presenter: Enriqueta Felip
Session: Poster Display session 1
Resources:
Abstract
1497 - Brigatinib (BRG) in Asian vs non-Asian patients (pts) with crizotinib (CRZ)-refractory ALK+ NSCLC in the phase 2 ALTA trial
Presenter: Dae Ho Lee
Session: Poster Display session 1
Resources:
Abstract
2349 - The safety assessment of crizotinib and alectinib from real world data of 840 ALK-inhibitor naïve patients with NSCLC harboring ALK-rearrangement (WJOG9516L).
Presenter: Kei Kunimasa
Session: Poster Display session 1
Resources:
Abstract
1120 - Brigatinib in ALK TKI-pretreated ALK+ metastatic non-small cell lung cancer (mNSCLC): the Use Via Expanded Access to Brigatinib (UVEA-Brig) study
Presenter: Silvia Novello
Session: Poster Display session 1
Resources:
Abstract
5239 - Treatment patterns and outcomes for patients (pts) with anaplastic lymphoma kinase-positive (ALK+) advanced non-small-cell lung cancer (NSCLC) in US clinical practice
Presenter: Matthew Krebs
Session: Poster Display session 1
Resources:
Abstract