New molecularly targeted therapies for lung cancer

Abstract

Lung cancer is the leading cause of cancer death worldwide. The disease is particularly difficult to detect, and patients often present at an advanced stage. Current treatments have limited effectiveness, and unfortunately, the prognosis remains poor. Recent insights into the molecular pathogenesis and biologic behavior of lung cancer have led to the development of rationally designed methods of early detection, prevention, and treatment of this disease. This article will review the important clinical implications of these advances, with a focus on new molecularly targeted therapies currently in development.

Figure 1. Novel therapies targeting key oncogenic pathways in lung cancer.

Several of the signaling and cell physiology pathways that are abnormal in lung cancer are depicted schematically along with drugs targeting components of these abnormal pathways. These drugs specifically target important molecules and pathways involved in lung cancer cell proliferation, inhibition of apoptosis, angiogenesis, and invasion and are currently in clinical trials for lung cancer. These include agents specifically inhibiting components of EGFR and other family members (such as ERBB2/Her2) and/or VEGFR pathways (with monoclonal antibodies and receptor TKIs or with inhibitors of key downstream pathway mediators such as the RAS/RAF/MEK or PI3K/Akt/mTOR pathway). Other agents in development include tumor suppressor gene (TSG) therapies, inhibitors of antiapoptotic proteins such as Bcl-2, HDAC inhibitors targeting the multiple epigenetic changes found in lung cancer, and proteasome (Pr) inhibitors. PDK1, pyruvate dehydrogenase kinase isozyme 1; PTEN, phosphatase and tensin homolog.

Figure 2. Cancer stem cell–specific therapeutic approaches.

Hedgehog (HH), Notch, and Wnt signaling are key stem cell self-renewal pathways that are deregulated in lung cancer and thus represent potential therapeutic targets (i). Agents inhibiting the hedgehog pathway include monoclonal antibodies against HH ligand and cyclopamine, which is a small molecule inhibitor of smoothened (SMO). Monoclonal antibodies against Wnt ligand and frizzled (FZD) receptor and inhibitors of protein complexes mediating Wnt signaling, such as Wnt-FZD or β-catenin–transcription factor (β-Cat-TCF), are examples of ways of targeting the Wnt pathway. Strategies of blocking or silencing Notch signaling can be either selective, such as the targeting of individual Notch receptors with antisense or monoclonal antibodies, or nonselective, such as the use of soluble receptor decoys that sequester Notch ligands or γ-secretase inhibitors. Solid and dashed arrows represent multiple components of these pathways that, for simplicity, are not detailed here. These components also represent potential therapeutic targets. Other methods of targeting cancer stem cells include immunotherapy-based approaches against antigens present on cancer stem cells (ii); targeting cancer stem cell mechanisms of resistance to cytotoxic therapy by inhibiting DNA repair enzymes such as the checkpoint kinases (Chk1, Chk2) (iii); targeting stem cell–specific survival mechanisms with telomerase inhibitors (GRN163L) (iv); and inducing stem cell differentiation with soluble factors such as bone morphogenetic proteins (BMPs) (v). GLI, glioma-associated oncogene; GLI^ACT, active form of GLI; GLI^REP, repressor form of GLI; NICD, Notch intracellular domain; CSL, CBF1, suppressor of hairless, Lag-1; TACE, TNF-α–converting enzyme; ADAM10, a disintegrin and metalloprotease domain 10; PTCH, patched homolog; GSK3β, glycogen synthase kinase 3β; CSK1α, cyclin-suppressing kinase 1; DSH, dishevelled.