Targeting mutations in cancer

Abstract

Targeted therapies have come to play an increasingly important role in cancer therapy over the past two decades. This success has been made possible in large part by technological advances in sequencing, which have greatly advanced our understanding of the mutational landscape of human cancer and the genetic drivers present in individual tumors. We are rapidly discovering a growing number of mutations that occur in targetable pathways, and thus tumor genetic testing has become an important component in the choice of appropriate therapies. Targeted therapy has dramatically transformed treatment outcomes and disease prognosis in some settings, whereas in other oncologic contexts, targeted approaches have yet to demonstrate considerable clinical efficacy. In this Review, we summarize the current knowledge of targetable mutations that occur in a range of cancers, including hematologic malignancies and solid tumors such as non-small cell lung cancer and breast cancer. We outline seminal examples of druggable mutations and targeting modalities and address the clinical and research challenges that must be overcome to maximize therapeutic benefit.

Figure 1. Timeline of FDA-approved targeted therapies in cancer.

FDA-approved molecules with mutation-specific indications are depicted along with their associated mutation-specific indications. First-in-class molecules for novel targets are shown in red.

Figure 2. Targeting modalities for targeted therapies in cancer.

Common modes of druggability associated with clinically approved molecules are depicted using the HER1/HER2 RTKs as examples. FDA-approved targeted therapies include small-molecule inhibitors and mAbs. Small-molecule inhibitors are commonly classified on the basis of the mechanism by which they bind their targets (inset). Small-molecule inhibitors in cancer can directly inhibit a mutant protein product, inhibit an overactive/overabundant protein product along with WT protein, or inhibit a signaling effector downstream of a mutated protein. In addition to inhibitors, mAbs are approved either with or without the addition of a drug conjugate, which, besides activating antibody-dependent cellular cytotoxicity (ADCC), also delivers cytotoxic payloads to targeted cells. DFG, aspartate-phenylalanine-glycine motif.

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.