Identification of Novel Alectinib-Resistant ALK Mutation G1202K with Sensitization to Lorlatinib: A Case Report and in silico Structural Modelling

Abstract

Ping Yang,1,* Ran Cao,2,* Hua Bao,2 Xue Wu,2 Lingling Yang,2 Dongqin Zhu,2 Lu Zhang,3 Liming Peng,4 Yuefei Cai,5 Weijun Zhang,6 Yang Shao2,7 1Department of Radiation Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong, People’s Republic of China; 2Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, People’s Republic of China; 3Department of Medical Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong, People’s Republic of China; 4Department of Respiratory Medicine, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong, People’s Republic of China; 5Department of Intervention, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong, People’s Republic of China; 6Departments of Radiation Oncology, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 7School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping YangDepartments of Radiation Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong, 523110, People’s Republic of ChinaEmail [email protected] ShaoNanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, People’s Republic of ChinaEmail [email protected]: Drug resistance caused by G1202R/G1202del mutation in anaplastic lymphoma kinase (ALK) represents a great challenge in the clinic. The effect of other mutation(s) at G1202 on the available tyrosine kinase inhibitors (TKIs) in the clinic remains unknown.Case Presentation: A 50-year-old Chinese male non-smoker with lung adenocarcinoma progressed with spinal metastasis after receiving chest radiation together with Pemetrexed and Cisplatin as adjuvant chemotherapy. Targeted next generation sequencing (NGS) identified EML4-ALK gene fusion in the resected left lung tissue. Local radiation followed by Crizotinib were used in the following treatment and the spinal metastasis was found to shrink, but the progression free survival (PFS) only lasted for 2 months with the appearance of brain metastasis. Afterwards, the patient benefited from the therapy of Alectinib with a PFS of 8 months. Then he progressed with metastases in right lung and pleural, and did not show response to the chemotherapy with Docetaxel plus Bevacizumab. The targeted sequencing consistently identified EML4-ALK gene fusion in both plasma and pleural effusion (PE), as well as a novel ALK G1202K mutation (c.3604_3605delGGinsAA). Given the lack of established or known drug treatment for this novel mutation, we implemented molecular dynamics (MD) simulation-guided drug sensitivity prediction, which results suggested Lorlatinib remains potent against G1202K mutant ALK. Therefore, Lorlatinib was used as the fourth-line therapy, which lead to the considerable efficacy with improved performance status (PS) score and reduced lung metastases. The structural mechanism underlying G1202K-induced drug resistance to different ALK-TKIs was also discussed.Conclusion: Our case suggested the ALK-G1202K mutation may serve as a novel mechanism underlying the resistance to Alectinib, and provide direct evidence to support its sensitization to Lorlatinib. Our work represented an example of integrating in silico predictions into clinical practice.Keywords: lung cancer, drug resistance, in silico prediction, binding energy calculation, Alectinib, Lorlatinib

Keywords

• lung cancer
• drug resistance
• in silico prediction
• binding energy calculation
• alectinib
• lorlatinib