Molecular‐targeted agents combination therapy for cancer: Developments and potentials

Abstract

Although chemotherapy has advanced into the era of targeted drugs, the antitumor efficacies of current therapies are limited, most likely because of the high degree of cancer clonal heterogeneity, intratumor genetic heterogeneity and cell signal complexity. As shutdown of a single target does not necessarily eradicate the cancer, the use of combinations of molecular-targeted agents (MATs) has been proposed, and some pioneering research has been conducted to examine the efficacy of this strategy. In this article, the clinical and preclinical studies that are underway in an attempt to improve the anticancer efficacy of chemotherapies through combination strategies are summarized. Studies of combining cytotoxic agents with MATs, coinhibiting two or more targets in a single pathway or coinhibiting parallel or compensatory pathways as well as specific combinations will be introduced, and the antitumor potentials of each combination strategy will be evaluated.

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

“…However, it is becoming increasingly clear that these signaling cascades form complex interacting networks that incorporate redundant signaling pathways, limiting clinical efficacy for single target-based drugs and promoting resistance to therapy (3,47). The optimal employment of combination therapies can enhance therapeutic responses in such scenarios by modulating the apoptotic balance to promote cell death.…”

“…However, the suppression of single cellular targets is unlikely to significantly extend disease-free survival for many cancer patients, as the amplification of redundant signaling pathways may allow for a negation of the inhibitory effect (2,3). This observation has prompted the development of combinatorial targeting strategies involving multiple oncogenic pathways to achieve more desirable outcomes (3).…”

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

“…Treatment of cancers is highly reliant on drug combinations, and drug synergies can be manifested through concomitant blockade of parallel signaling pathways or dual inhibition of the same pathway at distinct nodes (19). We performed a high-throughput combination screen to seek out therapeutic agents that combine synergistically with JAK inhibitors to kill human IL-2-dependent ATL cell lines.…”

Design, synthesis and biological activity of novel molecules designed to target PARP and DNA

“…Medical treatment of cancer is largely based on cytotoxic therapy involving DNA directed agents 66 (e.g cisplatin, cyclophosphamide, doxorubicin, temozolomide etc.). The major drawbacks of such therapies is their ability to block targets that are common to both normal and tumour cells.…”