EML4–ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7

O’Regan, Laura; Barone, Giancarlo; Adib, Rozita; Woo, Chang Gok; Jeong, Hui Jeong; Richardson, Emily L.; Richards, Mark W.; Müller, Patricia; Collis, Spencer J.; Fennell, Dean A.; Choi, Jiyoun; Bayliss, Richard; Fry, Andrew M.

doi:10.1242/jcs.241505

Cited by 34 publications

(37 citation statements)

References 57 publications

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“…The role of NEK9 in regulating microtubules may be directly related to its involvement in some types of cancer. A recent study showed that EML1-ALK variant 3, an oncogenic fusion present in non-small cell lung cancers, allows the recruitment of NEK9 and NEK7 proteins to microtubules via the N-terminal EML4 microtubule-binding region, leading to microtubule stabilization and increasing cell migration [187]. Beyond that, an elevation in NEK9 expression was associated with a reduction in progression-free survival in EML4-ALK patients.…”

Section: Nek9mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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Section: Nek9mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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“…Initially, NEK7 was thought to be the downstream target of WHSC1L1 involved in human carcinogenesis through expression profile analysis in vitro using human bladder and lung cancer cell lines (Kang et al, 2013). Similarly, in a recent study, EML4-ALK variant 3(V3) was proposed to mediate microtubule stabilization through NEK7 and NEK9, accelerating cell migration in EML4-ALK lung cancer (O'Regan et al, 2020). Another study found NEK7 is probably a downstream target gene of WHSC1 in multiple squamous cell carcinoma of the head and neck (SCCHN) cell lines as indicated via microarray expression profile analysis (Saloura et al, 2015).…”

Section: Nek7-regulated Mitosis and Nlrp3 Inflammasome In Diseases DImentioning

confidence: 99%

Physiological and Pathological Roles of Mammalian NEK7

2020

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NEK7 is the smallest NIMA-related kinase (NEK) in mammals. The pathological and physiological roles of NEK7 have been widely reported in many studies. To date, the major function of NEK7 has been well documented in mitosis and NLRP3 inflammasome activation, but the detailed mechanisms of its regulation remain unclear. This review summarizes current advances in NEK7 research involving mitotic regulation, NLRP3 inflammasome activation, related diseases and potential inhibitors, which may provide new insights into the understanding and therapy of the diseases associated with NEK7, as well as the subsequent studies in the future.

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“…Accumulating data from several retrospective analyses [ 23 , 24 , 94 , 95 , 96 , 97 ] and the randomized phase 3 study ALTA-1L [ 98 ] show that the “short” EML4-ALK fusion variant 3 (E6:A20, Figure 1 b) is associated with earlier treatment failure and shorter survival regardless of the type of treatment. V3-positive cases comprise approximately one-third of all ALK + NSCLC and present with more aggressive disease already at baseline, as evident by a higher number of metastatic sites at initial diagnosis [ 22 , 23 , 24 , 99 ]. Biochemical basis for this adverse clinical phenotype is the higher stability of shorter EML4-ALK variants, which leads to accumulation and stronger oncogenic signaling, as well as their better interaction with the cytoskeleton, which increases the migratory capacity of V3-positive cancer cells [ 22 , 100 ].…”

Section: State-of-the-art After the First Linementioning

confidence: 99%

Therapeutic Sequencing in ALK+ NSCLC

Elsayed

Christopoulos

2021

Pharmaceuticals

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Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.

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EML4–ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7

Cited by 34 publications

References 57 publications

Checking NEKs: Overcoming a Bottleneck in Human Diseases

Checking NEKs: Overcoming a Bottleneck in Human Diseases

Physiological and Pathological Roles of Mammalian NEK7

Therapeutic Sequencing in ALK+ NSCLC

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