The function of TKRs must be tightly regulated. Gain-Of-Function mutations in different regions of a receptor can alter this regulation and lead to an abnormal signaling that results in neoplastic growth. In the case of c-Kit, oncogenic mutations are frequent at exon 11 (coding for the JMD) and exon 17 (coding for the A-loop in the kinase domain). While the variants of exon 11 are prevalent in GIST and other solid tumors; leukemia and mastocytosis result from exon 17 mutations (Lennartsson & Ronnstrand, 2012). These c-Kit modifications determine the sensitivity or resistance to tyrosine kinase inhibitors such as imatinib (Frost et al., 2002).
The last part of this research was committed to studying the effects of c-Kit oncogenic mutations in cell spreading.
COS cells overexpressing either the c-KitW556A or c-KitD814V mutants showed a reduction in cell spreading. The mutation W556A had never been identified in human malignancies.
Nevertheless, other substitutions (human W557R) or deletions encompassing this residue are have been found in GISTs tumors (Willmore et al., 2004) as well as in malignant melanomas (Hodi et al., 2013) as a kinase-activating mutation. Because of its localization in the c-Kit JMD, we speculated that this hydrophobic residue might be involved in the regulatory function of this region. D816V.
Employing the tagRFP, we observed that both c-Kit versions mostly localized at the cytoplasm, a situation that can explain the lack of spreading response. A similar localization was observed in patients with GIST (S. Tabone-Eglinger et al., 2008). In this study, the authors showed that homozygous activating mutations are more frequently found in the nucleus than those in heterozygous state or the wild-type ones. The D816V mutant was also located intracellularly in the case of systemic mastocytosis (Bougherara et al., 2013). It has been shown that the c-Kit expression at the plasma membrane depends on its maturation at the ER (Brahimi-Adouane et al., 2013). It is, therefore, possible that such mutants are activated, phosphorylated and even degraded before reaching the plasma membrane.
Considering that a cytoplasmic expression might be responsible for lack of spreading, we studied the effect of treatment with imatinib and dasatinib in the spreading response. We carried on dose-response studies with TKIs which efficiently target specific c-Kit mutations.
After 1 hour of treatment, the cells were seeded on surfaces coated with fibronectin in the presence of immobilized-KitL. Different to MC/9 cells, COS cells overexpressing the WT receptor showed a reduced and delayed spreading from 10 µM of imatinib. Interestingly, although no significant, imatinib slightly increased the spreading response of cells expressing the mutant c-KitW556A. However, cells expressing the kinase active c-KitD814V were insensitive to this drug. Because dasatinib is more potent than imatinib in blocking SFK and c-Kit and recognizes the active form of TKR, we hypothesized that it might inhibit cell spreading induced by both ET and Kit activating mutants. Indeed, dasatinib significantly blocked c-KitWT-mediated spreading from 100nM. However, it was less effective than imatinib in recovering the spreading of c-KitW556A expressing cells.
These results suggest that imatinib which is effective against regulatory mutants (W556A?) but not the catalytic ones (D814V) is also effective in recovering cell spreading. Likely imatinib induces the relocation of the W556A to the cell membrane while is less efficient in changing the expression of the mutant D814V. To note that in the case of a WT receptor, imatinib leads to the receptor degradation and internalization without KitL stimulation (D'Allard et al., 2013).
To confirm these observations, we pretreated cells with imatinib or dasatinib for 2h and 3h.
With this treatment regimen, we could increase the spreading of W556A expressing cells (data not shown). Unfortunately, this is preliminary data and we need to go further with the additional spreading test. In parallel, a potential imatinib-induced relocation of W556A to the cell membrane should be confirmed by FACS and immunofluorescence.
By combining various methods to analyze and compare the native and mutated c-Kit, the present study demonstrated that both the JMD (W556A) and the A-loop (D814V) mutants do have the same effect in cell spreading. However, their sensitivity to tyrosine kinase inhibitors vaguely differs. The differences in drug sensitivity need to be confirmed by using other TKIs (e.g., nilotinib or sunitinib), dasatinib being able to block spreading of non-transfected cells.
For example, nilotinib which succeeded in patients with imatinib-resistant melanoma carrying c-Kit mutations (Carvajal et al., 2015). It will be useful to test whether the human mast cell lines (HMC) expressing the activating mutations V560G (HMC-1) and V560G and D816V (HMS-1.2) (I. J. Chan et al., 2013) respond as COS cells overexpressing such c-Kit variants. It seems that the phenomenon of re-spreading of an activated c-Kit receptor induced by imatinib is correlated with the inhibition of their kinase activity. It remains to be confirmed whether this response is associated with de-phosphorylation of c-Kit and the associated signaling proteins.
What is the mechanism by which these mutants interfere with cell spreading?
In the c-Kit auto-inhibitory state, the JMD inserts into the catalytic site preventing the A-loop from switching into its extended active conformation (Mol et al., 2004; Mol et al., 2003). The c-Kit D816V mutant destabilizes the A-loop that in turns release the JMD from its inhibitory conformation and activates the kinase (Laine et al., 2011). DiNitto et al. demonstrated that the active c-Kit D816V mutant cannot bind neither imatinib nor sunitinib and the phosphorylation of Y823 in the A-loop is prevented. They also showed that the c-Kit Y823F affects the sensitivity to drugs and can bind imatinib as well as sunitinib (DiNitto et al., 2010).
The authors suggested that by interfering with the phosphorylation of Y823, the receptor can alternate between an inactive and an active state changing its sensitivity to imatinib. When we overexpressed c-KitY823F in COS cells, spreading on fibronectin was abolished entirely. It is possible that by destabilizing the A-loop mutations in this region the hierarchy of tyrosine phosphorylation is modified. Consequently, the phosphorylation of Y821, which occurs very late after c-Kit activation, might happens in first place. If this is the case, it could block the recruitment of PI3K in Y719 in the kinase insert, therefore, preventing cell spreading.
Concerning the A-loop, further experiments will be addressed to confirm whether there is a different mechanism of c-Kit activation, between soluble- and immobilized-Kit ligand?
In this research work, we have studied the implication of the c-Kit signaling in integrin-dependent adhesion of c-Kit expressing cells. We have also explored the effects of c-Kit kinase inhibition and conclude that Dasatinib is the only drug capable of inhibiting spreading towards an immobilized-KitL in fibronectin-poor surfaces. By introducing mutations in different regions of c-Kit, we observed that oncogenic variants of c-Kit drastically blocked cell spreading. The same response was followed by interfering with the recruitment of PI3K and by destabilizing the A-loop. Molecular and functional studies need to be done to unravel the mechanism by which c-Kit and integrins collaborate in mediating cell spreading and their sensitivity to kinase inhibition. The high spreading in the presence of imatinib argues for a function of c-Kit in mediating the anchorage of malignant cells to their respective niches even in the absence of a functional kinase. Such an adhesive phenotype might favor the resistant of tumor cells to therapy and the disease relapse. Thus, the elucidation of the mechanism that regulates cell-niche interactions is an essential aspect of the tumor biology so that news
"successfully targeted" therapies can be designed.
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