Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

Abstract

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. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods: We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results: The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38-and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions: These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

“…Some examples are the inhibitors of Axl (NCT03184558), VEGFR (NCT03394287, NCT03797326) and c-Kit (NCT03855358). Furthermore, there is a rapid increase of the number of studies showing the efficacy of co-blocking PD-1, or its ligand, and RTKs in various human cancers [14][15][16][17], including TNBC [18].…”

Clinic-pathological characteristics of MMR protein, KRAS-NRAS-BRAF gene mutation, HER-2 and PD-L1 status in 3822 Chinese colorectal cancer patients

“…It is of great clinical signi cance to study its expression in colorectal cancer for its pathogenesis and future treatment. In colorectal cancer, there are a few inconsistencies in the prognosis of PD-L1 [32,33] . Our data showed that PD-L1 expression was signi cantly higher in d-MMR patients.…”

“…Interaction of PD-1 and PD-L1 inhibits T-cell activation and cytokine production. PD-L1 is induced by many cytokines, such as interferon-γ (IFN-γ), signal transducer and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR), transforming growth factor β (TGFβ), and hypoxia inducible-factor-1α (HIF-1α) [10] . In normal immune system, PD-1/PD-L1 pathway activation will inhibit the immune function of T lymphocytes and promote the inhibitory function of regulatory T cells, which can reduce the immune response.…”

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

“…Some examples are the inhibitors of Axl (NCT03184558), VEGFR (NCT03394287, NCT03797326) and c-Kit (NCT03855358). Furthermore, there is a rapid increase of the number of studies showing the e cacy of co-blocking PD-1, or its ligand, and RTKs in various human cancers [14][15][16][17], including TNBC [18].…”