The ALK oncogene (Anaplastic Lymphoma Kinase) is a constitutively active tyrosine kinase involved in an increasing number of cancers. Initially identified as being responsible for the majority of pediatric anaplastic large cell lymphomas, its involvement in a wider spectrum of tumours such as inflammatory myofibroblastic tumours, certain B lymphomas, colon cancers, neuroblastomas and in 5% of non-small cell lung cancers (NSCLC) has now been demonstrated. Thus, the number of patients presenting with cancers dependent on the ALK oncogene continues to increase each year. These tumours are treated by chemotherapy, which is not an optimal treatment (relapse of the disease, reduced quality of life).
Anaplastic large cell lymphomas expressing the ALK oncogene develop mainly in children and young adults. Crizotinib was the first inhibitor targeting ALK to be used clinically in refractory or relapse cases after conventional chemotherapy treatment of these patients. Unfortunately, relapses on Crizotinib are still observed.
Autophagy is a self-digestion mechanism by which the cell is able to degrade its own constituents (cytoplasm, defective cell organelles, toxic protein aggregates…), by sequestering them and then transporting them to lysosomes (the cell organelle responsible for degrading macromolecules by means of enzymes). This self-destructive cellular process, when pushed to the extreme, could help eradicate tumour cells and thus prevent the recurrence of the disease.
In a recent publication published in the journal Cancers, Dr Sylvie Giuriato (CRCT team 8, led by Dr Stéphane Manenti) has shown that the combined inhibition of the proto-oncogene NPM-ALK (by Crizotinib) and RAF1 (by Vemurafenib or other molecular strategies reducing the level of RAF1 expression) strongly activates autophagy, which is then associated with the death of tumour cells.
This work demonstrates the efficacy of a new therapeutic combination, Crizotinib + Vemurafenib, two known pharmacological inhibitors, for the treatment of ALK-positive anaplastic large cell lymphoma. They also confirm that therapeutic targeting of autophagy could improve the treatment of these patients. These results pave the way for new research targeting the autophagy process in order to better understand and prevent tumour relapse in anaplastic large cell lymphoma and, more broadly, in other cancers dependent on the ALK oncogene.
Discover the published articles
Cancers (Basel). 2020 Oct 13;12(10):E2951.doi: 10.3390/cancers12102951.
High Levels of miR-7-5p Potentiate Crizotinib-Induced Cytokilling and Autophagic Flux by Targeting RAF1 in NPM-ALK Positive Lymphoma Cells
Domenico Sorrentino, Julie Frentzel, Géraldine Mitou, Rafael B Blasco, Avédis Torossian, Coralie Hoareau-Aveilla, Chiara Pighi, Manon Farcé, Fabienne Meggetto, Stéphane Manenti, Estelle Espinos, Roberto Chiarle, Sylvie Giuriato
Key Words :
- Anaplastic large cell lymphoma ALK positive ;
- NPM-ALK ;
- Autophagy;
- Cell death;
- Combined therapy;
- Crizotinib;
- microRNA ;
- RAF1 ;
- Vemurafenib
Collaborations and partnerships :
- This work was carried out in collaboration with the team of Dr Roberto Chiarle (Boston Children Hospital, Boston, MA, USA).
- This work was funded by the European Horizon 2020 programme, Marie Sklodowska-Curie ITN No 675712 (S.G. and D.S.) ; by the NCI/NIH R01CA196703 (R.C.) ; by a label from the National League Against Cancer (S. M.) ; by the Regional League Against Cancer R12020BB and the ARC Foundation R15002BB (S.G.) ; by the National League Against Cancer (J.F.) ; by the ANR JCJC R12004BB (G.M.) and the French Society of Hematology (D.S.)
Contact :
Dr Sylvie GIURIATO
CRCT Team 8: ” Cell cycle, autophagy and cancer “, directed by Dr Stéphane MANENTI
Mail: sylvie.giuriato@inserm.fr
One picture :
Effect of the combined inhibition of the oncogene NPM-ALK and RAF1 on the autophagy flux and on the cell fate of ALK-positive anaplastic large cell lymphoma.
Targeted inhibition of NPM-ALK by crizotinib has been shown to induce protective autophagy for tumour cells. This response is associated with a decrease in the level of expression of microRNA-7-5p (miR-7) and an increase in the expression of one of its targets: RAF1. Molecular (miR-7 mimics or siRAF1) or pharmacological (Vemurafenib) inactivation of RAF1, combined with the inhibition of NPM-ALK (Crizotinib) induces a potentiation of autophagy, which then assumes cytotoxic properties. Co-treatment with Crizotinib + Vemurafenib, by modulating the intensity and functions of autophagy, therefore appears superior to crizotinib alone in the treatment of ALK-positive anaplastic large cell lymphomas.
