A close link with a key player in tumour progress

Why do cells survive longer when the protein KIAA1199 is more expressed? Because it stabilizes a receptor well known to cancer specialists: EGFR (epidermal growth factor receptor). “When this receptor is stabilised, it is active and induces survival and cell invasion. On the other hand, when it is destabilised and no longer functional, cells die”, Alain Chariot points out. Furthermore, in parallel to the activation of this cell survival signalling pathway via EGFR, the protein KIAA1199 also limits some cell death pathways. “More specifically, it prevents semaphorin 3A from triggering a series of reactions leading to cell death”, the researcher specifies.

By establishing this link between the protein KIAA1199 and EGFR, scientists have pinpointed a key mechanism in the development of cervical cancers, a mechanism that is most likely relevant to many other types of cancers. “All solid tumours in which EGFR has a constitutive activity may also rely on KIAA1199 for their growth. In this case, cancers of the lung, pancreas or glioblastoma”, Alain Chariot emphasises. “In other types of cancer in which activating EGFR mutations are rarely found, it is other members of this family of receptors that are amplified. This is especially true for the HER-2 gene in 15 % of breast tumours. It is likely that they also need the protein KIAA1199 to induce cell survival and invasion signals". Hence, the identification of this “simple” connection between KIAA1199 and EGFR is relevant for a whole array of cancers and could therefore be an interesting avenue for the treatment of many people.

Overcoming the resistance of cancerous cells

Since research in molecular biology succeeded in defining EGFR as a key player for the development of numerous solid tumours, this receptor has become one of the therapeutic targets in the treatment of these tumours.

There are currently specific inhibitors for EGFR. They are administered to patients suffering from tumours exhibiting a high activity of this receptor. “Following the treatment, tumour regression is significant. But after a few weeks, the cancerous cell – which has a high level of plasticity – can establish a genetic program to escape from cell death triggered by the chemotherapy and this is certainly true for EGFR inhibitors”, Alain Chariot explains. “Cancer cells find other means to activate parallel pathways to circumvent the blockage of EGFR activity.” This strategy allows cancerous cells to become resistant, thus leading to a relapse. “We are beginning to identify these parallel pathways”, the scientist continues. “We now know at least three brothers and sisters of EGFR that can be hyperactivated in cancerous cells in which EGFR activity is blocked”. We can therefore understand the interest of targeting KIAA1199. Indeed, by preventing this protein’s action, not only will this lead to the destabilisation – and hence, inhibition – of EGFR, but also that of other members of its family. Therefore, none of these receptors will send survival and invasion signals to cancerous cells anymore. “We believe that it’s worth trying to find a way to inhibit the protein KIAA1199 to overcome resistance to treatment against EGFR”, the specialist emphasises.