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
5437 - Salivary cytokines and oral mucosa cells apoptosis in patients during hematopoietic cell transplantation: possible relationship with oral mucositis
Presenter: Luciana Corrêa
Session: Poster Display session 1
Resources:
Abstract
1483 - A randomized trial of sodium alginate prevention of radiation-induced esophagitis in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy: OLCSG1401
Presenter: Toshihide Yokoyama
Session: Poster Display session 1
Resources:
Abstract
2047 - Taste and smell alterations (TSAs) in patients (pts) with stage II-III colon cancer (CC): a pilot within the PROTECT study
Presenter: Jeroen Derksen
Session: Poster Display session 1
Resources:
Abstract
5984 - Clinical characteristics are associated with acupuncture treatment response for xerostomia in cancer patients
Presenter: Wenli Liu
Session: Poster Display session 1
Resources:
Abstract
2845 - Psychosocial Distress of Adolescent and Young Adults with Cancer at Diagnosis: A Case-Matched Retrospective Cohort of 2045 Patients in British Columbia.
Presenter: Alannah Smrke
Session: Poster Display session 1
Resources:
Abstract
724 - Accuracy of distress thermometer to measure cancer-related mood disorders in Chinese patients with cancer
Presenter: Sudip Thapa
Session: Poster Display session 1
Resources:
Abstract
2357 - Modalities of biosimilar filgrastim use in clinical practice in >1000 patients receiving chemotherapy regimens with a rest period of ≤14 days: the TOPAZE study
Presenter: Jean Marc Phelip
Session: Poster Display session 1
Resources:
Abstract
1426 - The Effect of Increasing Doses of Pegfilgrastim (Peg) on Thrombocytopenia (T) in Breast Cancer (BC) Patients (pts) Receiving Taxotere (Doc), Doxorubicin, Cyclophosphamide (TAC) and Plinabulin (Plin)
Presenter: Douglas Blayney
Session: Poster Display session 1
Resources:
Abstract
712 - The use of intravenous ferric carboxymaltose without erythropoiesis-stimulating agents in the treatment of anemia in cancer patients undergoing chemotherapy with or without radiotherapy
Presenter: Hikmat Abdel-Razeq
Session: Poster Display session 1
Resources:
Abstract
1496 - Randomized, double-blind, cross-over Phase I study comparing pharmacokinetics, pharmacodynamics, safety and immunogenicity of a biosimilar pegfilgrastim with EU and US references
Presenter: Maria Velinova
Session: Poster Display session 1
Resources:
Abstract