Inhibitors of the centrosome-duplicating protein PLK4 selectively target cells with high TRIM37 expression.

  • Major Finding: Inhibitors of the centrosome-duplicating protein PLK4 selectively target cells with high TRIM37 expression.

  • Concept:TRIM37, encoding a centrosomal ubiquitin ligase, is elevated in copy number in breast cancer, neuroblastoma, and other cancers.

  • Impact: This uncovers mechanisms of PLK4 inhibitors' effects and suggests a patient group that may benefit.

Inhibitors of PLK4, a serine/threonine protein kinase critical for duplicating the microtubule-organizing centrosomes that facilitate mitosis, are under investigation as anticancer agents. Complementary studies by Yeow, Lambrus, and colleagues and Meitinger and colleagues uncovered a role for the centrosomal ubiquitin ligase TRIM37 in mediating the effects of PLK4 inhibition. In breast cancer cells and patient-derived organoids, Yeow, Lambrus, and colleagues found that PLK4 inhibitors were effective in the context of TRIM37 amplification or overexpression; notably, TRIM37 amplification (due to chromosome 17q23 amplification) occurs in 10% of breast cancers. PLK4 inhibitor treatment interfered with mitotic spindle assembly across multiple breast cancer cell lines that harbored 17q23 amplification, causing mitotic catastrophe and cell death. These defects were attributed to TRIM37 overexpression. TRIM37 depletion rescued normal bipolar spindle formation in PLK4 inhibitor–treated cells; in untreated 17q23-amplified cell lines, it reduced the frequency of chromosome missegregation events and other mitotic errors. TRIM37 overexpression reduced levels of proteins that comprise the pericentriolar material (PCM), including CEP192, PCNT, and CDK5RAP2. PCM depletion observed with TRIM37 overexpression caused delayed and defective microtubule nucleation in mitosis, an effect attributed to a complete loss of mitotic PCM foci, structures that acted as microtubule organizing centers in centrosome-depleted cells. Concurrently, Meitinger and colleagues discovered sensitivity to PLK4 inhibition of both 17q23-amplified breast cancer and neuroblastoma cell lines (50% to 60% of neuroblastomas exhibit gain of chromosome arm 17q). TRIM37 exerted bidirectional control over mitosis in PLK4-inhibited cells. Whereas TRIM37 overexpression led to catastrophic mitotic failure in cells treated with a PLK4 inhibitor, loss of TRIM37 accelerated spindle assembly in and increased the proliferation of PLK4-inhibited cells. TRIM37 overexpression reduced formation of PCM foci in mitosis and led to lower levels of the PCM protein CEP192. In coexpression experiments, TRIM37 interacted with CEP192, and its ligase activity promoted CEP192 ubiquitination and reduced stability. In both studies, CEP192 knockdown recapitulated the synthetic-lethal effect of TRIM37 overexpression in PLK4 inhibitor–treated cells. Together, these two studies elucidate much of the biology underlying PLK4 inhibitors' mechanism of action and suggest a patient population for whom they may be of interest.

Yeow ZY, Lambrus BG, Marlow R, Zhan KH, Durin MA, Evans LT, et al. Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer. Nature 2020 Sep 9 [Epub ahead of print].

Meitinger F, Ohta M, Lee KY, Watanabe S, Davis RL, Anzola JV, et al. TRIM37 controls cancer-specific vulnerability to PLK4 inhibition. Nature 2020 Sep 9 [Epub ahead of print].

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