Figure 3. Mechanisms of resistance to targeted therapies against kinases in cancer.

In response to kinase inhibitors, mutations in the kinase domain that prevent drug binding to the target are the most frequent resistant mechanisms. Other mechanisms of resistance to kinase inhibition include alterations in drug transport or metabolism and mutations in either downstream pathway effectors or alternative signaling pathway effectors. Resistance also occurs with mAbs targeting kinases, with loss/downregulation/truncation of the targeted antigen being the most common. Resistance mechanisms that affect both small-molecule inhibitors and mAbs are also common and include phenotypic transformation, tumor heterogeneity, immune dysregulation, and microenvironmental upregulation of ligands/growth factors.