Abstract
Polo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, PLK2 (chromosome 5q11.2) is frequently deleted in human breast cancers, preferentially in basal-like and triple-negative breast cancer subtypes. Here, we found that PLK2 was tumor suppressive in breast cancer and knockdown of PLK1 rescued phenotypes induced by PLK2-loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase and that mutations in the kinase domain of PLK2, but not polo-box binding domains, changed their interaction pattern. Furthermore, treatment of syngeneic transplantation mouse tumor models and patient-derived xenografts using the PLK1 inhibitor volasertib alone, or in combination with carboplatin, indicated that PLK2-low breast tumors had a significantly better response to these drugs. Re-expression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. Taken together, our data suggest PLK2 loss may serve as a biomarker to predict response to PLK1 therapeutics, alone and in combination with chemotherapy.
Significance The tumor suppressive role of PLK2, and its relationship with the oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2 low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.
Competing Interest Statement
C.M. Perou is an equity stockholder and board member of BioClassifier and GeneCentric Therapeutics. C.M. Perou is also listed as an inventor on patent applications for the Breast PAM50. M.T. Lewis is a Founder and Limited Partner of StemMed Ltd, and a Manager of StemMed Holdings, LLC, its General Partner. M.T. Lewis is also a Founder of, and equity holder in, Tvardi Therapeutics Inc. The other authors declare that they have no competing interests.
Footnotes
Disclosure of Potential Conflicts of Interest C.M. Perou is an equity stockholder and board member of BioClassifier and GeneCentric Therapeutics. C.M. Perou is also listed as an inventor on patent applications for the Breast PAM50. M.T. Lewis is a Founder and Limited Partner of StemMed Ltd, and a Manager of StemMed Holdings, LLC, its General Partner. M.T. Lewis is also a Founder of, and equity holder in, Tvardi Therapeutics Inc. The other authors declare that they have no competing interests.