Background
Altered regulation of tyrosine kinase receptors is frequent in solid tumors and it is often associated with the acquisition of an aggressive phenotype. Thus, therapies targeting these receptors have been proposed as molecular approaches to treat human cancers. Despite the initial enthusiasm for the efficacy of these therapies, clinicians had to face soon the problems of lack of clinical response in some patients (primary resistance) and of relapse to treatment, as almost invariably cancer patients develop drug resistance (secondary resistance). It is therefore important to understand the mechanisms of resistance to molecular targeted therapies, in an effort to optimize the outcome of the treatments.
Achievements
The evidence that Met is at the crossroad of several pathways involved in tumorigenesis and progression toward metastasis prompted us to study if tumors cells may be dependent (or “addicted”) to the uninterrupted activity of this oncogene. We showed indeed that in some tumor cells the persistent activity of the Met oncogene is required for tumor growth and for metastasis formation and persistence, in spite of the many genetic lesions harbored by cancer cells. Moreover, we have recently shown that “addicted” tumor cells may become “resistant” to therapies targeting MET and we have identified some mechanisms underlying resistance to treatment.
Goals
We aim at studying molecular mechanisms that allow tumor cells to become insensitive to molecular targeted therapies. We have recently identified some genetic alteration of cells unresponsive to anti-MET therapies, such as amplification of MET and other oncogenes or engagement of alternative or redundant survival pathways. We now want (i) to understand the molecular mechanisms leading to resistance to treatment (ii) evaluate, in this context, the role of epigenetic modifications of gene encoding for proteins or for microRNAs; (iii) investigate strategies to overcome the resistance (use of inhibitors of downstream targets; study of differential sensibility of resistant cells to chemotherapics).
Internal collaborations
Laboratory of Cellular Biology: role of semaphorins in cancer; Laboratories of Genetics and Oncogenomics, Pathology and Molecular Oncology: resistance to targeted therapies.
