EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.05.010

Authors: Kei Kunimasa, Yosuke Hirotsu, Yoji Kukita, Yumi Ueda, Yoshiharu Sato, Madoka Kimura, Tomoyuki Otsuka, Yuichiro Hamamoto, Motohiro Tamiya, Takako Inoue, Takahisa Kawamura, Kazumi Nishino, Kenji Amemiya, Taichiro Goto, Hitoshi Mochizuki, Keiichiro Honma, Masao Omata and Toru Kumagai

Case StudyKirk SmithMay 10, 2021EML4-ALK, ALK inhibitor, Co-occurrent mutation, PIK3CA, primary resistance

Primary Resistance to Brigatinib in a Patient with Lung Adenocarcinoma Harboring ALK G1202R Mutation and LIPI-NTRK1 Rearrangement

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors have transformed the management of non-small-cell lung cancer (NSCLC) patients with ALK gene rearrangement. This paper reports a new resistance mechanism to a second-generation ALK inhibitor, brigatinib. Case Report: A 43-year-old woman who had no history of smoking was diagnosed with stage IVa (T2bN2M1b) lung adenocarcinoma. After the first-line chemotherapy failed, the patient received crizotinib due to the presence of EML4-ALK fusion by next-generation sequencing (NGS). The patient had disease progression after 8 months on crizotinib, and a second NGS identified the ALK G1202R resistance mutation. Therefore, she was switched to brigatinib. After only 53 days of treatment with brigatinib, the patient developed a new 1.6× 1.2 cm lesion in the mediastinal lymph node. A third NGS testing revealed a new form of NTRK rearrangement (LIPI-NTRK1). The patient died 16 months after diagnosis.Conclusion: This paper provides new insights into ..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S249652

Authors: Xiao Z, Huang X, Xie B, Xie W, Huang M, Lin L.

Case StudyKirk SmithMay 22, 2020LIPI-NTRK1, ALK, primary resistance, brigatinib, NSCLC