Pocket Oncology (Pocket Notebook Series), 1st Ed.

GROWTH FACTOR SIGNALING

Alexander Drilon

Oncogenes vs. Tumor Suppressor Genes (TSGs)

• Oncogenes: Contribute to the development or maintenance of the neoplastic phenotype, converted from protooncogenes w/c have nl functions that are involved in cell differentiation, proliferation, & apoptosis → these may sustain gain-of-function or activating Mt that result in constitutive activation (NEJM 2008;358:502)

Oncogene addiction: Process by w/c tumor cells become highly dependent on an oncogenic protein or pathway for sustained proliferation or survival, 1° driver Mt in oncogenes are often mutually exclusive (Cancer Res 2008;68:3077)

Many oncogenes encode growth factor receptors or proteins involved in cell signaling

• TSGs: Encode proteins responsible for inhibiting tumor formation or maintenance, involved in processes like DNA repair & apoptosis

Growth Factor Signaling

• Initiated by ligand binding to growth factor receptors that activate downstream pathways; mechanism by w/c an extracellular signal is transduced through a cell, resulting in a change in gene expression, modifying specific cellular processes

• Can be targeted by mAbs (eg, bevacizumab for VEGF, cetuximab for EGFR, see Monoclonal Antibodies Chap.) or small molecules (eg, TKIs)

Figure 4-4 Growth factor signaling: Ligand binding (eg, EGF, TGFα, epiregulin) → receptor dimerization & phosphorylation of intracellular TK domains → downstream pathway activation; ↑ pathway activity mediated by signal transduction proteins (protooncogenes) of MAPK and PI3K pathways, negative regulators (TSGs) shown in white → ultimately affect processes such as cell survival & proliferation, differentiation, angiogenesis, etc.