Since the initial clinical approval in the late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served as a fundamental backbone in precision medicine for cancer treatment. These approaches are now used clinically as first-line therapy for various types of human cancers. Compared to conventional chemotherapy, targeted therapeutic agents have efficient anticancer effects with fewer side effects. However, the emergence of drug resistance is a major drawback of molecular targeted therapy, and several strategies have been attempted to improve therapeutic efficacy by overcoming such resistance. Herein, we summarize current knowledge regarding several targeted therapeutic agents, including classification, a brief biology of target kinases, mechanisms of action, examples of clinically used targeted therapy, and perspectives for future development.

Cancer is a leading cause of disease-related mortality worldwide. Drug resistance is one of the primary reasons for the failure of anticancer therapy. There are a number of underlying mechanisms for anticancer drug resistance including genetic/epigenetic modifications, microenvironmental factors, and tumor heterogeneity. In the present scenario, researchers have focused on these novel mechanisms and strategies to tackle them. Recently, researchers have recognized the ability of cancer to become dormant because of anticancer drug resistance, tumor relapse, and progression. Currently, cancer dormancy is classified into “tumor mass dormancy” and “cellular dormancy.” Tumor mass dormancy represents the equilibrium between cell proliferation and cell death under the control of blood supply and immune responses. Cellular dormancy denotes the state in which cells undergo quiescence and is characterized by autophagy, stress-tolerance signaling, microenvironmental cues, and epigenetic modifications. Cancer dormancy has been regarded as the stem of primary or distal recurrent tumor formation and poor clinical outcomes in cancer patients. Despite the insufficiency of reliable models of cellular dormancy, the mechanisms underlying the regulation of cellular dormancy have been clarified in numerous studies. A better understanding of the biology of cancer dormancy is critical for the development of effective anticancer therapeutic strategies. In this review, we summarize the characteristics and regulatory mechanisms of cellular dormancy, introduce several potential strategies for targeting cellular dormancy, and discuss future perspectives.

Cancer is the leading cause of human deaths worldwide. Understanding the biology underlying the evolution of cancer is important for reducing the economic and social burden of cancer. In addition to genetic aberrations, recent studies demonstrate metabolic rewiring, such as aerobic glycolysis, glutamine dependency, accumulation of intermediates of glycolysis, and upregulation of lipid and amino acid synthesis, in several types of cancer to support their high demands on nutrients for building blocks and energy production. Moreover, oncogenic mutations are known to be associated with metabolic reprogramming in cancer, and these overall changes collectively influence tumor-microenvironment interactions and cancer progression. Accordingly, several agents targeting metabolic alterations in cancer have been extensively evaluated in preclinical and clinical settings. Additionally, metabolic reprogramming is considered a novel target to control cancers harboring un-targetable oncogenic alterations such as KRAS. Focusing on lung cancer, here, we highlight recent findings regarding metabolic rewiring in cancer, its association with oncogenic alterations, and therapeutic strategies to control deregulated metabolism in cancer.

Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, it is necessary to develop effective mitochondria-targeting anticancer drugs. By screening a large chemical library consisting of natural products with diverse chemical entities, we identified gracillin, a steroidal saponin, as a mitochondria-targeting antitumor drug. Gracillin displayed broad-spectrum inhibitory effects on the viability of a large panel of human cancer cell lines, including those carrying acquired resistance to chemotherapy or EGFR-targeting drugs, by inducing apoptosis. We show that gracillin attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and by producing reactive oxygen species (ROS). Mechanistically, gracillin disrupts complex II (CII) function by abrogating succinate dehydrogenase (SDH) activity without affecting the succinate:ubiquinone reductase. The gracillin-induced cell death was potentiated by 3-nitropropionic acid (3-NPA) or thenoyltrifluoroacetone (TTFA), which inhibit CII by binding to the active site of SDHA or to the ubiquinone-binding site, respectively. Finally, we show that gracillin effectively suppressed the mutant-Kras-driven lung tumorigenesis and the growth of xenograft tumors derived from cell lines or patient tissues. Gracillin displayed no obvious pathophysiological features in mice. Collectively, gracillin has potential as a CII-targeting antitumor drug.