![]() ![]() Large-scale genomic studies are bringing the genetic basis of NB into focus, and there is evidence to suggest that high and low-risk forms of the disease evolve through distinct genetic mechanisms 5. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. While low- and intermediate-risk forms of NB are highly curable, over half of patients with high-risk disease suffer relapse and five-year survival is 40–50% 4. Characterized by heterogeneous biological and clinical features ranging from spontaneous regression to aggressive treatment-resistant disease, NB is often referred to as a clinical enigma. ![]() NB presents at various sites along the sympathoadrenal axis, most commonly in the adrenal medulla or paraspinal ganglia 3. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.ĭeriving from precursor cells of the sympathetic nervous system, neuroblastoma (NB) is the most common and deadly extracranial solid tumor in children 1, 2. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |