Abstract
Emerging drug-resistance and drug-associated toxicities are two major factors limiting successful cancer therapy. Combinations of chemotherapeutic drugs have been used in the clinic to improve patient outcome. However, cancer cells can acquire resistance to drugs, alone or in combination. Resistant tumors can also exhibit cross-resistance to other chemotherapeutic agents, resulting in sub-optimal treatment and/or treatment failure. Therefore, developing novel oncology drugs that induce no or little acquired resistance and with a favorable safety profile is essential. We show here that combining COTI-2, a novel clinical stage agent, with multiple chemotherapeutic and targeted agents enhances the activity of these drugs in vitro and in vivo. Importantly, no overt toxicity was observed in the combination treatment groups in vivo. Furthermore, unlike the tested chemotherapeutic drugs, cancer cells did not develop resistance to COTI-2. Finally, some chemo-resistant tumor cell lines only showed mild cross-resistance to COTI-2 while most remained sensitive to it.
Highlights
Emergence of drug-resistant clones and treatment-associated toxicities are two major barriers to successful cancer treatment [1]
Combining Critical Outcome Technologies Inc. (COTI)-2 with paclitaxel and cisplatin enhances their activity in small cell lung cancer cells
COTI-2 was further evaluated in combination with paclitaxel in a human endometrial tumor model since paclitaxel is commonly used in the management of endometrial cancer [15]
Summary
Emergence of drug-resistant clones and treatment-associated toxicities are two major barriers to successful cancer treatment [1]. Drug resistance can result in rapid disease progression either during or shortly after completion of treatment. Cytotoxic anticancer drugs designed to inhibit growth of fast-dividing tumor cells are often not target-specific and are limited by their off-target toxicities. Precision medicine drugs are designed to be target-specific and to induce fewer undesirable side effects than conventional chemotherapy. Cancer cells often develop resistance to targeted agents [2]. Combining two or more agents with unrelated
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