Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Abstract

Anti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast-and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

“…Neopeptides associated to somatic mutations were generated as decribed in ref. 73 . Note that we had to discard~1.2% of somatic mutations because of inconsistencies between the variant annotation (this can be for either somatic variants or germline variants occurring on the same transcripts as the somatic ones) and the refseq_cds.txt file (GRCh37/hg19 Feb 2009) we used for generating the neopeptides.…”

“…As HLA-presented neopeptides, we picked all core peptides (see ref. 73 ) with a percentile rank <0.5%. MLH1 promoter qPCR.…”

Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond

“…Interestingly, the CMS are associated with specific immune and stromal profile [67,68]. The CMS was developed using a set of localized tumors and its value in the metastatic setting remains controversial: (i) spatial CMS heterogeneity has been described, as some tumors have a homogeneous CMS and others have a heterogeneous CMS, which complicates the allocation of tumors to a specific group and modulate the prognosis [69]; (ii) CMS modifications has been observed within metastatic tumor under active antitumoral treatment such as anti-EGFR agents [70]. Consequently, CMS clinical applicability in the metastatic setting remains limited and even reinforced by the complexity of bioinformatical analyses.…”

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

“…CRC cell types defined by oncogenic signal activities and differentiation states may therefore provide opportunities to study mechanisms of resistance defined by CRC cell plasticity. Recent studies already point to roles of paracrine signals and the microenvironment in anti-EGFR therapy resistance of CRC 50,51 . Our CRC cell classification system could therefore aid in building a comprehensive subtyping system for CRC on the single cell level with therapeutic relevance.…”