Reference Detail

Ref Type

PMID

(33790576)

Authors

Yang P, Cao R, Bao H, Wu X, Yang L, Zhu D, Zhang L, Peng L, Cai Y, Zhang W, Shao Y

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
OncoTargets and therapy	14		2021	2131-2138	Onco Targets Ther

URL

Abstract Text

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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	G1202K	missense	unknown	ALK G1202K lies within the protein kinase domain of the Alk protein (UniProt.org). G1202K has been identified in the scientific literature (PMID: 33790576), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Nov 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1202K	lung adenocarcinoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, fourth-line Lorbrena (lorlatinib) treatment resulted in symptom improvement and response in lung disease with a progression-free survival lasting 4 months in an EML4-ALK positive a patient with lung adenocarcinoma patient harboring EML4-ALK and an acquired ALK G1202K, who had previously progressed on Xalkori (crizotinib) and Alecensa (alectinib) treatment (PMID: 33790576).	33790576