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be done in investigating mechanisms of innate or acquired resistance to immunotherapy in these subgroups
of tumours.

CMS2 cancers have low mutation rate compared to CMS1 and in most cases no mutations of BRAF and
RAS are detected. Typically MYC and WNT pathways are activated so multiple efforts to interact with these
[6]
signal transduction cascades should be considered . For patients with KRAS, NRAS, BRAF and PIK3CA
wild-type tumours (almost 30% of all cases), anti-EGFR antibody in combination with chemotherapy
should remain the standard of care though retrospective analysis from the main phase III trials suggested
differential benefit of anti-EGFR treatment according to primary tumour sidedness [83,84] . Anti-EGFR benefit
seems to be restricted to patients with distal primary tumor with overexpression of EGFR ligands and
[85]
amplifications of EGFR and IRS2 .

CMS3 cancers are characterized by KRAS mutations (almost 68%) and enriched for multiple metabolism
[6]
signatures including glutamine, fatty acid and lysophospholipid metabolism . Most CMS3 cancers don’t
have an easily identifiable therapeutic target but trials ongoing are evaluating the potential inhibition of these
metabolic processes with glycolysis inhibitors such as inhibitors of glycogen synthase kinase or inhibitors of
pyruvate dehydrogenase kinases. For tumours with HER-2 overexpression (3%-5% of this group), anti-HER2
and pan-ERBB TKI combination should overcome primary resistance to anti-EGFR treatment. Furthermore,
in KRAS mutated cell lines, preclinical trials suggested that combination of pan-RAF and MEK inhibitors
[47]
may be considered .

As mentioned above, CMS2 and CMS3 tumours are so called “cold” or immune-ignorant tumours.
Multiple clinical trials are evaluating combinations of chemo-immunotherapy and targeted agents and
immunotherapy (anti MEK + anti PDL-1, CEA-CD3 TCB + anti PDL-1, anti-EGFR + anti-PD1) after negative
results of previous trials with anti-PD1 and anti-PDL1 as monotherapy. Some interesting suggestions with
COX-inhibitors, HDAC inhibitors should be confirmed by future phase III trials.

For CMS4 group, the identification of actionable targets is of major interest considering the worse relapse-
free and overall survival. These tumours, characterized by mesenchymal stem-cell features, seems to have no
[86]
benefit from standard adjuvant therapy with 5-FU and oxaliplatin because of EMT activation .

For BRAF mutated tumours, target combination therapies with BRAF-inhibitors and MEK-inhibitors have
[88]
[87]
shown lower clinical benefit than in melanoma . In a recent clinical experience by Kopetz et al. , the
addition of anti-EGFR to the previous combination seems to be more effective.

Combinations of TGFR inhibitors and chemotherapy are under evaluation in ongoing clinical trials for
tumours with “TGF-B activated” signature. The pro-cancerogenic effect of TGF-B develops through a direct
effect on cancer cells but also on immune cells with inhibition of CTLs and NK cells associated with an
expansion of Treg cells and MDSCs. In preclinical trials, combination of TGFR-B inhibitor with an OX40
agonistic mAb or with anti-PD1, showed a potential synergistic effect with high tumour-specific IFNg
[89]
esponse .

Another possible target could be angiogenesis: the subgroup analysis of CALGB 80404 trial confirmed
[40]
clinical benefit with bevacizumab especially in CMS4 group . Furthermore retrospective analysis from
Correct trial with Regorafenib (multiple TKIs that targets VEGFR1-2-3) highlighted CMS4 group as the one
[90]
who benefits the most from this treatment .

The efficacy of check-point inhibitors in this subgroup of patients is limited by the intense
immunosuppressive response in the tumour microenvironment.