Research ArticleCancer

Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials

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Science Translational Medicine  11 Sep 2019:
Vol. 11, Issue 509, eaaw8412
DOI: 10.1126/scitranslmed.aaw8412

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  • RE: Horiuchi et al.

    I largely agree with the comments published by Horiuchi et al. As we wrote in the discussion section of this paper, “our findings may provide evidence that cancer drug polypharmacology is a common MOA for reportedly target-specific compounds.” That is, one potential explanation for our results is that drugs reported to be specific for certain proteins, like PIM1 or caspase-3, may in fact also target their close homologs. We showed that PIM1 is non-essential in 32 different cancer cell lines, but we agree that it could be the case that there is synthetic redundancy between PIM1, PIM2, and PIM3. As Horiuchi et al. suggest, multiplex knockdown- or knockout-approaches will be needed to test this possibility.

    Regarding the PIM inhibitors: SGI-1776 was reported to exhibit 50-fold selectivity for PIM1 over PIM2 and 10-fold selectivity for PIM1 over PIM3 (Chen et al., Blood 2009). The other inhibitors mentioned (AZD1208, LGH447, and INCB053914) were never reported to be selective for PIM1, and so we did not study them. I agree with Horiuchi et al. that our experiments do not rule out the possibility that SGI-1776, AZD1208, or any of these drugs function by blocking all three PIM kinases. Our results simply demonstrate that the specific inhibition of PIM1 by SGI-1776 is unable to account for its anti-cancer properties. I am excited to see how the pan-PIM inhibitors behave in clinical trials, though the severe cardiotoxicity observed with SGI-1776 indicates that caution is...

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    Competing Interests: None declared.
  • RE: Lin et al. (2019) Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.
    • Dai Horiuchi, Assistant Professor, Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    • Other Contributors:
      • Sarki A. Abdulkadir, Professor, Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
      • Varsha Gandhi, Professor, Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA
      • Andrei Goga, Professor, Departments of Cell & Tissue Biology and Medicine, University of California, San Francisco, CA 94143
      • Andrew Tutt, Professor, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK

    All authors contributed to this eLetter equally.

    Lin et al. shed light on the idea that targeted therapeutic agents can fail during clinical evaluations because the primary mechanisms of drug action are either not well understood or misunderstood. However, it appears significantly more data would be needed to support some of the authors’ core suggestions.

    The authors recognized several factors that are currently considered to be potential anticancer targets, such as those that may need to be reevaluated as viable anticancer targets. One of these protein targets is PIM1, which belongs to the PIM family of serine/threonine kinases, which is composed of three closely related isoforms, PIM1, PIM2, and PIM3 [1]. The authors used the CRISPR deletion approach to show that selective PIM1 knockout (KO) did not significantly inhibit the proliferation of some breast cancer cell lines. The authors also showed that PIM1-KO cells were as sensitive as PIM1-wild-type cells to the first-generation, pan-PIM kinase inhibitor SGI-1776 [2], leading them to suggest that SGI-1776 may exert its antitumor effects through yet-to-be-identified off-target mechanisms of drug action. While this particular early PIM inhibitor may have targets beyond PIM kinases, there are more parsimonious explanations for the authors’ observations that suggest their conclusions may require reassessment.

    First, all the clinically relevant PIM kinase inhibitors, (SGI-1776 [2], AZD1208 [3], LGH447/PIM...

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    Competing Interests: None declared.

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