NEK2, a promising target in TP53 mutant cancer.

In human cancers, aberration of tumor suppressors and oncogenes cooperate to contribute to tumor initiation and progression.[1,2]TP53, one of the best-known tumor suppressors, appears to have diverse roles through working together with different oncogenes.[3,4] A good example is RAS mutations co-occurring with TP53 lesions. KRAS hyper-activation leads to cell replicative senescence, which could be overcome by lesions in TP53, escaping immune clearance surveillance and promoting tumorigenesis. In the current issue of Adv Sci 2022, Feng et al expand the significance of TP53 loss to drug resistance through co-regulating oncogene NEK2 amplification/gene overexpression with multiple myeloma (MM) as a disease model.[5]

In this paper, the authors set out the study with systematic identification of the correlation between TP53 genetic lesion and amplification/overexpression of NEK2 in MM through data mining of public available datasets. This led to the discovery of co-occurrence between TP53 deletion and NEK2 amplification/ overexpression, which is significantly associated with poor overall survival in MM. Of note, this synergy is a shared feature across various cancer types as TCGA data reanalysis confirmed this observation, indicating a high priority to understand the molecular mechanism for this co-occurrence as well as its clinical implication (Fig. 1).

Figure 1

TP53 genetic lesions promote NEK2 abundance by regulating gene expression and oncogene amplification. TP53 genetic lesions employ multiple molecular mechanisms to regulate NEK2 abundance, which either by increasing promoter hypermethylation to control gene expression or by inducing chromosomal instability to modulate copy number of NEK2. Combined defects in TP53 and NEK2 render multiple myeloma cells drug resistance to Bortezomib.

The authors first established a causal relationship between TP53 deletion and NEK2 gene overexpression/amplification using MM cell lines with and without TP53 allele. Loss of TP53 gene led to differential expression of genes involved in cell cycle, methylation control, and chromosomal stability, resulting in the transcriptional hyper-activation of NEK2 through down-regulating methyltransferase (eg, DNMT) and up-regulating E2F genes. Moreover, TP53 loss also promoted the acquisition of multiple copies of NEK2 by increasing genomic instability. Consequently, NEK2 activation and TP53 suppression caused mitotic aberrations, tumor proliferation, and disease progression in MM. All these phenotypes can be reversed by overexpression of wildtype p53, highly suggesting that TP53 loss unleash NEK2 amplification/overexpression to boost cancer cell genomic instability and proliferation. NEK2 was previously reported to induce drug resistance through activation of efflux drug pumps.[6] The authors then tested if TP53 loss/NEK2 overexpression may form the basis of drug resistance to contribute to the disease aggressiveness. Using MM front line therapy Bortezomib (BTZ) as an example, they demonstrated that silencing of NEK2 in TP53 depleted MM cells sensitized these cells to the drug treatment and impaired cell proliferation. Stable expression of wildtype p53 enhanced the therapeutic effect of BTZ both in vitro and in vivo with further improvement upon NEK2 depletion. Altogether, these results suggest that targeting the function of the NEK2 and p53 pathways may have therapeutic values by reversing the adverse outcome of MM patients without p53.

As one of the most frequently mutated/deleted tumor suppressors in cancer, TP53 genetic lesions are often associated with poor overall survival; hence, it is a good therapeutic target. However, most of the lesions produce generally inactive proteins, making it challenging with drugs. The current strategy has been focusing on restoring wildtype p53 function with small molecules or other means.[7-10] This discovery illustrates that targeting NEK2 kinase in TP53 mutated/depleted cancers could be an alternative strategy. In this light, the development on NEK2 kinase inhibitors and testing their efficacy alone and in combination with gold standard treatment would be a priority in MM and maybe other tumor types. In this scenario, investigation of synergy between lesions in TP53 and NEK2 in other tumoral contexts would be beneficial. Although a causative link was established in this current study, some MM samples with TP53 deletion but without NEK2 overexpression/amplification remains to be further investigated for their antagonist mechanism (s) in controlling this synergy.