Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

ML-3 A Case of Primary Central Nervous System Anaplastic Lymphoma Kinase Positive Anaplastic Large cell Lymphoma at Neurohypophysis and Pineal Gland

The majority of primary central nerve system (CNS) lymphomas (PCNSL) are diffuse large B-cell lymphomas. Anaplastic large cell lymphoma (ALCL) that is a type of T-cell tumor is very rare in the PCNSL. ALCLs are divided into two entities: anaplastic lymphoma kinase (ALK)-positive and ALK-negative. We report a case of a 26-year-old woman who presented with a one month historyof headache and nausea. Magnetic resonance imaging (MRI) of the brain revealed pituitary and pineal gland mass diagnosed as ALK-positive ALCL by endoscopic brain biopsy. She underwent chemotherapy following methotrexate (MTX) and cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP). The follow-up contrast-enhanced brain MRI showed no recurrent lesion after chemotherapy. In previous reports, most of the lesions were in cerebral hemisphere, dura mater and spinal cord. Many of these patients were given primary diagnoses of meningitis. To our knowledge, there is no case report of initial diagnosis of germinoma due to lesions in Neurohypophysis and pineal gland as in this case.