Thanks to a very efficient experimental model, a group of Italian researchers led by Carla Boccaccio of the Cancerf Stem Cell Research Laboratory of the IRCCS Candiolo Cancer Institute showed that even tumors of unknown origin, or CUP, could have an ‘Achilles heel’: a MEK inhibitor, trametinib, induces CUP-derived agnospheres cell death in vitro and necrosis of experimental CUP tumors. The data, published in Nature Communications (https://www.nature.com/articles/s41467-021-22643-w), pave the way for new treatment options and Gianni Bonadonna Foundation is also actively involved in the development of new treatments for patients.
Researchers isolated a panel of human CUP-initiating stem-like cells, named agnospheres, or spheroids enriched in CUP-derived stem cells, and studied their genetic and molecular profile to define pathways mostly involved in proliferative autonomy typical of CUP. «We observed a constitutive activation of the proliferative MAP kinase pathway, sustaining expression and activity of the MYC proto-oncogene», Carla Boccaccio says. «MEK inhibition with trametinib causes agnosphere cell death, and necrosis of experimental CUP tumors, without inducing negative feedback mechanisms: ‘turning off’ MYC removes from CUP something that underlies its ability to propagate. Now we are trying to better understand the details of this ‘dialogue’ between MEK and MYC, but it seems clear that CUPs do not have other cancer adaptive mechanisms to compensate for any inhibition of MEK “.
Trametinib is already used in metastatic melanomas with BRAF oncogene mutation and as Boccaccio specifies «CUPs share similarities with metastatic melanoma, which spreads elsewhere when it’s very small. All this is very interesting because it also shows that it’s not necessary to hypothesize ‘special’ transduction pathways for metastasis: probably what induces them is the combination of known factors in a specific context, for example the presence of cells that combine stem cell properties and proliferative capacity. Cancer cells always spread around the body, the real ‘leap’ towards metastasis occurs when they are able to stop and proliferate. To do this, perhaps they need very well known molecular mechanisms such as the MEK / MYC pathway activation». These data are a step forward in CUP understanding; the hope, shared by Bonadonna Foundation, is to set-up clinical trials with trametinib, more MYC-targeted drugs or drugs designed against other essential actors of this molecular pathway.