​​​​​​​ Br J Cancer 2017. doi:10.1038/bjc.2017.353

As BRAF is downstream of RAS in the MAPK/ERK signalling axis,  BRAF -mutated cancers would be expected to display a similar degree of resistance to anti-EGFR therapy as  RAS -mutated cancers.

Their findings indicate that the EGFR mutational status can be accurately ascertained using tumour-derived cfDNA from pleural effusion fluid, and is correlated with responsiveness to EGFR tyrosine-kinase inhibitors (TKIs) 9 .

B-cell receptor signalling inhibitors Aberrant activation of the B-cell receptor (BCR) signalling pathway is implicated in the pathogenesis and progression of a variety of B-cell malignancies2.

EGFR  is amplified in about 2% of breast cancers 1 , and is overexpressed more frequently in BLBC than in non-BLBC.

Based on preclinical data supporting the interaction between inihibition of PARP and the VEGF signalling pathway (Pyriochou et al , 2008; Yadav et al , 2011), a phase I study was conducted to evaluate veliparib in combination with a platinum/taxane regimen plus bevacizumab in epithelial ovarian fallopian or primary peritoneal cancer ( N =189) (Bell-McGuinn et al , 2015).

The construct is composed of a single-chain variable fragment (scFv) of an antibody fused to the activating intracellular-signalling domain of the T-cell receptor (TCR), typically the ζ signalling domain (Figure 2a). 10, 11, 12 Polyclonal CAR T cells recognize their target antigen through the antibody domain resulting in T-cell activation independent of major histocompatibility complex (MHC) presentation. 13 The scFvs are constructed by cloning the heavy and light chain variable regions of an antigen-specific monoclonal antibody, separated by a short peptide linker, into a single polypeptide. 14, 15, 16 DNA encoding this construct can be transduced ex vivo using transfection, gamma retroviral or lentiviral recombinant vectors, or a transposon system. 17, 18, 19,20, 21, 22 Various CAR-T-cell constructs exist with distinct scFvs and signalling domains (Figure 2b).

Although not achieving statistical significance, mutations in the mTOR signalling pathway genes TSC1 , TSC2 and MTOR were also identified in chRCC.

Given the disappointing results obtained with farnesyltransferase inhibition, further avenues of targeting the RAS-signalling pathway have been explored, predominantly inhibition of downstream mediators, such as MEK and AKT — with a preclinical rationale for dual-pathway inhibition 114 .