Abstract 4156
Background
Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic Colorectal Cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway.
Methods
In order to understand the mechanism underlying MEK inhibitor (MEKi) resistance, we generated three different MEKi resistant models, two all RAS WT (SW48-MR and LIM1215-MR) and one mutated in RAS (HCT116-MR).
Results
These models showed features related to the gene signature of Colorectal Cancer CMS4 with upregulation of immune pathway as confirmed by Microarray and Western blot analysis. In particular, moving forward the MEKi phenotype we assisted to the loss of epithelial features and acquisition of mesenchymal markers and morphology. Moreover, this change in the morphology is accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently of cell line status mutation. To extend these in vitro findings, we performed an in vivo study using MC38 and CT26 MEKi resistant syngeneic models that we have previously generated. Combined treatment of MEKi, EGFR inhibitor (EGFRi) and PD-L1inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both MC38–MR and CT26-MR xenograft model.
Conclusions
These results suggest a strategy to potentially overcome immunotherapy resistance in CMS4-like tumors and to improve the efficacy of MEK inhibition by co-treatment with other agents providing an additional therapeutic strategy via modulation of host immune responses.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3930 - Safety profile of tepotinib in patients with advanced solid tumors: pooled analysis of phase I and II data
Presenter: Thomas Decaens
Session: Poster Display session 1
Resources:
Abstract
5373 - Drug-drug interaction profile of tepotinib with CYP3A and P-gp substrates
Presenter: Juergen Heuer
Session: Poster Display session 1
Resources:
Abstract
5455 - Bioavailability of tepotinib: impact of omeprazole and food
Presenter: Juergen Heuer
Session: Poster Display session 1
Resources:
Abstract
2618 - Tislelizumab Exposure-Response Analyses of Efficacy and Safety in Patients with Advanced Tumors
Presenter: Chi-Yuan Wu
Session: Poster Display session 1
Resources:
Abstract
2563 - Population Pharmacokinetics of Tislelizumab in Patients with Advanced Tumors
Presenter: Chi-Yuan Wu
Session: Poster Display session 1
Resources:
Abstract
2021 - The Addition of Metformin to Systemic Anticancer Therapy
Presenter: Jung Han Kim
Session: Poster Display session 1
Resources:
Abstract
5243 - Growth modulation index (GMI) as a comparative measure of clinical activity of larotrectinib versus prior systemic treatments in adult and pediatric TRK fusion cancer patients
Presenter: Antoine Italiano
Session: Poster Display session 1
Resources:
Abstract
598 - Analysis of the overall survival and main surrogates used for FDA approvals in solid and hematological malignancies.
Presenter: Maria Kleniewska-Wieczor
Session: Poster Display session 1
Resources:
Abstract
5381 - Comparison of intratumoral docetaxel exposure in cancer patients between nanoparticle entrapped docetaxel (CPC634) and conventional docetaxel (Cd): the CriTax study
Presenter: Ruben Van Eerden
Session: Poster Display session 1
Resources:
Abstract
2935 - Correlation of progression free survival-2 and overall survival in solid tumors
Presenter: Paul Mainwaring
Session: Poster Display session 1
Resources:
Abstract