Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma

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ABSTRACT A specific subset of T cell lymphoma (TCL) called Anaplastic Large Cell Lymphoma (ALCL) frequently harbors chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene. Chemotherapy is the current standard of care for ALK+ ALCL, but fails in approximately 30% of patients. Most ALK+ ALCL that fail chemotherapy respond well to the ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, with higher responses in children than in adults and FDA agency recently granted the breakthrough therapy designation for crizotinib for the treatment of patients with relapsed/refractory ALK+ ALCL. Based on these exciting results, it is not impossible to think that in the future ALK TKIs will become the first-line therapy for ALCL, thus overcoming the long-term toxicity of chemotherapy. A similar switch has happened in the case of ALK+ non- small cell lung cancer (NSCLC) that is currently treated in first-line with ALK TKIs. Despite most ALK+ ALCL patients refractory to chemotherapy achieve complete remission when treated with ALK TKIs, still a fraction of patients quickly develop resistance. In addition, responder patients are not completely cured as discontinuation of crizotinib is associated with rapid lymphoma relapse even after many years of complete remission with undetectable disease. Therefore, ALCL can develop molecular mechanisms that protect lymphoma cells from the activity of ALK TKIs. To achieve the ambitious goal of treating ALK+ ALCL with targeted therapy and replace chemotherapy as much as possible, there is need to completely understand these mechanisms that lead to ALK TKI resistance in ALCL. By genetic screenings, extensive sequencing and mouse models, we identified three main mechanisms leading to ALK TKI resistance and possibly sustaining the long-term persistence of ALCL cells: - we identified a phosphatase-mediated mechanism when we discovered that PTPN1 and PTPN2 are phosphatases of ALK and together with the SHP2 phosphatase regulate the sensitivity of ALCL cells to ALK TKIs; - we discovered that activation of PI3Kγ signaling supports survival of persister cells during ALK inhibition; - we elucidated the key role of the Rho family GTPases to mediate ALK signaling in ALCL. For this project, we hypothesize that targeting these three main pathways with specific combined therapies could cope with resistance and lead to the eradication of persister cells for a complete cure of ALK+ ALCL. In this project, we will validate this concept with in vitro and in vivo models that will be used to test different therapeutic strategies. Thus, ALK+ ALCL could become the first T cell lymphoma to be completely cured without chemotherapy, with obvious long-term benefits for children and adults affected by this disease. In addition, our results could pave the way to broaden these therapeutic concepts to other incurable TCL.