Upgrading gemcitabine with recycled kinase inhibitors

Despite recent advancements in the development of targeted cancer therapies, cytotoxic DNA-damaging agents still dominate medical oncology's arsenal for the treatment of many malignancies. One cytotoxic agent, gemcitabine (2′,2′-difluorodeoxycytidine), is a nucleoside analog that has been part of the standard of care for pancreatic cancer patients since 1997.1 Upon cellular uptake, gemcitabine is readily metabolized to its triphosphate form and incorporated into nascent DNA, thus disrupting DNA replication and resulting in programmed cell death.2,3 The overarching mechanism of action of gemcitabine is that, like most cytotoxics, it kills rapidly cycling cells. Our intricate understanding of the post-translational modifications that control cell cycle dynamics have opened a unique opportunity to utilize gatekeeper kinase inhibitors as chemosensitizers. For instance, it has been shown that overriding the DNA damage checkpoint by forcing cells into mitosis can lead to mitotic catastrophe and enhance cytotoxic chemotherapy.4 In fact, this is the basis for the recent development of WEE1 and CHK1 kinase inhibitors, as both kinases are master cell cycle checkpoint regulators,4,5 particularly in the setting of p53-deficiency. Launching off this concept, Beeharry et al. screened 9 clinically available kinase inhibitors to optimize gemcitabine for the treatment of pancreatic cancer cells. Through cell-based, molecular modeling, and biochemical assays, BEZ-235, dovitinib, and bosutinib were identified as effective sensitizers for gemcitabine. Bosutinib, an FDA-approved Src/Abl kinase inhibitor, was the most potent and specific and thus became the focus of the study. These compelling findings open a new pipeline and avenue for repurposing kinase inhibitors for clinical use. Drug recycling is a fast track approach to making a difference in the clinic and can save significant amounts of time and money on drug development. In fact, it has been estimated that from bench to bedside a novel compound can take up to a decade and cost up to a billion dollars to get through Phase I – III clinical trials. These drug repurposing and validation studies such as the one presented in this issue of Cell Cycle leaves us wondering whether drug companies are too quick to perform ‘hit and run’ studies with a number of FDA-approved compounds. How many FDA-approved inhibitors are pigeon-holed into a very specific indication, that when repurposed in alternative settings could broaden the drug's indication? Moreover, how many drugs “failed” in clinical development and have been relegated to the “pharmaceutical junk yard,” that when repurposed with the correct treatment combination could have had the potential to make a difference? For example, the authors serendipitously discovered that Bosutinib (and the Bosutinib isomer, Bos-I, which was sold to the research community as authentic Bosutinib) can dually inhibit CHK1 and WEE1, with Bos-I showing greater potency in pancreatic cancer cells. These drugs are not as potent as real CHK1 and WEE1 inhibitors; rather it's their ability to inhibit both kinases that make these compounds work as sensitizers. In line with current clinical studies testing the anti-tumor activity of WEE1 and CHK1 kinase inhibitors,6 the prospect of introducing Bos-I into the clinic is rather appealing because it targets both of these kinases at once in a highly effective manner. Importantly, in vivo studies using patient-derived xenograft models demonstrated that Bos-I administered in conjunction with low-dose gemcitabine significantly suppressed tumor growth through a mechanism that was convincingly demonstrated to involve CHK1 and WEE1 inhibition. It would be intriguing now to assess the clinical utility of Bos-I beyond optimizing gemcitabine, as it may potentially be used in conjunction with other current standard of care therapies such as gemcitabine plus nab-paclitaxel or FOLFIRINOX.7 It is important to note that a previous Phase I clinical trial was set up to test the combination of authentic Bosutinib and gemcitabine. However, clinicaltrials.gov claims the study was terminated due to insufficient accrual (only 3 patients). Thus, unless discontinued for safety reasons (and the dose might have been based on Bosutinib labeled as a Src/Abl inhibitor), the clinical potential of this combination has not been properly tested. Amid our excitement exist a number of challenges to moving a recycled compound from the bench to the bedside. First, the concept of taking a cytotoxic agent with known, albeit limited, activity such as gemcitabine and optimizing it with recycled kinase inhibitors may not be deemed innovative enough by research funding agencies. Second, large pharmaceutical companies may be hesitant to sponsor large clinical trials with kinase inhibitors that may have previously failed in the clinic or may no longer have any intellectual property associated with it. Third, as observed with Bosutinib, it is imperative to identify the off-target effects of seemingly “specific” kinase inhibitors in order to understand whether they can be used as sensitizing agents in the clinic. Fourth, getting approval for off-label drug use can be challenging both from the FDA and unwilling insurance providers. It is expected that by 2020, pancreatic cancer will become the second most lethal cancer in the United States (Pancreatic Cancer Action Network). As we eagerly wait for development of targeted therapeutics, digging into the recycling bin may provide a creative, fast-track approach to enhancing current therapies for this lethal disease. The obvious next step is to both refine the identified compound(s) and set up a pilot early phase clinical trial. Unfortunately, with today's climate the recycled question is: Who will pay for all this?