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Page 74 Shek et al. Cancer Drug Resist 2019;2:69-81 I http://dx.doi.org/10.20517/cdr.2018.20

Figure 2. Mechanism of anticancer activity of anti-EGFR mAbs. Cetuximab and panitumumab bind to EGF receptors, thus preventing
further signalling transduction via PI3K/mTOR and RAS/ERK pathways. Inactivation of growth signalling pathways prevents cell
proliferation and survival. EGFR: epidermal growth factor receptor; mAbs: monoclonal antibodies

PART 2. THE INFLUENCE OF GENETIC POLYMORPHISMS ON MONOCLONAL ANTIBODY
TREATMENTS
Association of growth signalling pathways with monoclonal antibodies response
Mutations within growth signalling pathway genes are essential to fuel cancer development and progression.
One such pathway that is targeted by mAb therapy is the EGFR pathway. Following EGF or Transforming
growth factor alpha (TGFa) binding, EGFR signalling drives metastasis, proliferation and angiogenesis
[42]
through activation of the Ras/Raf/ERK and PI3K/AKT/mTOR signalling pathways . Anti-EGFR mAbs,
such as cetuximab and panitumumab prevent receptor-ligand interactions, thus inhibiting downstream
activation of growth signalling pathways [Figure 2].

Current pharmacogenetic research approaches have aimed to examine the potential relationship between
somatic mutations in the Ras/Raf/ERK and PI3K/AKT/mTOR pathways, with efficacy of anti-EGFR mAbs
used for treatment of colorectal cancer (cetuximab, panitumumab). Genetic polymorphisms of the gene
encoding Raf protein (BRAF) are very crucial for cancer treatment with anti-EGFR mAbs, with BRAF
[43]
mutations occurring in 4%-11% of patients with colorectal cancer . In particular, BRAFV600E (rs113488022)
is associated with an aggressive tumour phenotype, early lymph node metastasis and reduced response to
[44]
cetuximab and panitumumab treatment . A meta-analysis of 10 clinical trials has shown that cetuximab
and panitumumab treatment did not improve PFS, overall survival (OS) and response rate in 462 colorectal
cancer patients with BRAFV600E mutation (rs113488022) when compared to the control group treated by
[44]
[44]
standard chemotherapy . In the same study, Pietrantonio et al. have shown that patients without the
BRAFV600E mutation were associated with lower risk of progression (P = 0.001) and higher response to
cetuximab and panitumumab treatment (P = 0.001), compared to those with mutation. Interestingly, the
BRAFV600E mutation has been shown to destabilise the inactive conformation of the Raf protein, rendering
[45]
the new mutated protein in a constitutively active state . Consequently, upstream inactivation of EGFR
signalling via mAb treatment would have minimal therapeutic effect, explaining the clinical findings.

Several studies have examined the correlation between genetic polymorphisms affecting PI3K/mTOR
signalling pathway and anti-EGFR mAb treatment. This pathway plays a crucial role in regulating the cell