Turning liabilities into opportunities: Off-target based drug repurposing in cancer

Abstract

Targeted drugs and precision medicine have transformed the landscape of cancer therapy and significantly improved patient outcomes in many cases. However, as therapies are becoming more and more tailored to smaller patient populations and acquired resistance is limiting the duration of clinical responses, there is an ever increasing demand for new drugs, which is not easily met considering steadily rising drug attrition rates and development costs. Considering these challenges drug repurposing is an attractive complementary approach to traditional drug discovery that can satisfy some of these needs. This is facilitated by the fact that most targeted drugs, despite their implicit connotation, are not singularly specific, but rather display a wide spectrum of target selectivity. Importantly, some of the unintended drug "off-targets" are known anticancer targets in their own right. Others are becoming recognized as such in the process of elucidating off-target mechanisms that in fact are responsible for a drug's anticancer activity, thereby revealing potentially new cancer vulnerabilities. Harnessing such beneficial off-target effects can therefore lead to novel and promising precision medicine approaches. Here, we will discuss experimental and computational methods that are employed to specifically develop single target and network-based off-target repurposing strategies, for instance with drug combinations or polypharmacology drugs. By illustrating concrete examples that have led to clinical translation we will furthermore examine the various scientific and non-scientific factors that cumulatively determine the success of these efforts and thus can inform the future development of new and potentially lifesaving off-target based drug repurposing strategies for cancers that constitute important unmet medical needs.

Keywords: Drug repurposing; Off-target; Polypharmacology; Precision medicine; Targeted cancer therapy.

Figure 1.. On-target and off-target based drug repurposing.

A. Cartoon illustrating the repurposing of drugs (A; B) for different cancers based on their intended targets A and B playing a functional role in cancer. The initial indication may be another cancer or a cancer-unrelated disease. B. Cartoon illustrating the repurposing of a multi-targeted drug (C) for a specific type of cancer based on inhibition of an off-target (G) that plays a functional role in that cancer. The initial indication may be another cancer or a cancer-unrelated disease.

Figure 2.. Single target and network pharmacology strategies for cancer therapy.

A. Monotherapy for targeting a single, strong oncogene driver leading to cancer cell death. B. Network-based targeting strategies for cancers and inhibition of oncogenic pathways driven by multiple oncoproteins of varying strength (arrow width) can be implemented either by combination therapy with more than one drug (upper panel) or by a single drug with polypharmacology mechanism of action against more than one cancer-relevant target (lower panel).

Figure 3.. Off-target based drug repurposing initiatives for dasatinib and ibrutinib in various cancers.

A. Repurposing of the dual SRC/ABL inhibitor, developed to treat CML, for various B cell malignancies and NSCLC due to its ability to also inhibit BTK and EGFR (weak), respectively. Combination therapy with the potent EGFR TKI erlotinib led to the identification of mutant DDR2 as a novel cancer driver in LUSQ. B. Repurposing of the irreversible BTK inhibitor ibrutinib, developed to treat different B cell malignancies, for breast cancer (with trastuzumab) and EGFR-mutant NSCLC due to its ability to also inhibit HER2 and EGFR, respectively. * indicates oncogenic mutation; ** indicates gene amplification; light bulb indicates discovery of new drug-protein interaction.