Speaker
Description
Anaplastic lymphoma kinase (ALK) gene rearrangement, representing 3 - 7% of NSCLC, was identified as an oncogenic driver in 2007 [1]. It typically comprises younger patients with never or light smoking history [1,2]. The labs of Choi and Buettner have made significant contributions in profiling this molecular subtype as their institutions have one of the largest collections of this rare entity in each of the nations. We have previously reported that p53-mutant ALK-rearranged NSCLC cases have a much shorter benefit from tyrosine kinase inhibitors (TKIs) compared to p53-wildtype tumors due to genomic instability and amplifications on myc or alterations of TERT [3-5]. Using Korean samples, Dr. Choi has reported that EML4-ALK variant 3 tumors exhibit more aggressive tumor progression and worse prognosis than EML4-ALK variant 1 NSCLCs [6]. Additionally, ALK-rearranged NSCLC shows upregulation of integrin β3 compared to other subtypes of NSCLC, which was associated with ALK inhibitor resistance [7]. Although efforts have been made to dissect the genomic profiles of ALK-rearranged NSCLC, as shown from previous studies reported by both groups, the clinical responses can vary significantly even within the ALK-rearranged NSCLC, and there is no clear stratification of patients who will enjoy the maximum benefit of ALK inhibitors. Notably, until now, studies reporting of the genomic profiles in ALK-rearranged NSCLC were based on the utilization of bulk tumor sequencing. Sequencing using bulk tissue has become the standard. However, rare genomic alterations with the potential to higher functional significance may be masked by tissue homogenization, thereby obscuring the actual tumor heterogeneity. Through our collaboration, we were able to explore the molecular profiles using spatial transcriptomics and compare the genomic profile between the two ancestrally differing cohorts.
References
- Soda, M.; Choi, Y.L.; Enomoto, M.; Takada, S.; Yamashita, Y.; Ishikawa, S.; Fujiwara, S.; Watanabe, H.; Kurashina, K.; Hatanaka, H.; et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007, 448, 561-566, doi:10.1038/nature05945.
- Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014, 511, 543-550, doi:10.1038/nature13385.
- Alidousty, C.; Baar, T.; Martelotto, L.G.; Heydt, C.; Wagener, S.; Fassunke, J.; Duerbaum, N.; Scheel, A.H.; Frank, S.; Holz, B.; et al. Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations. J Pathol 2018, 246, 67-76, doi:10.1002/path.5110.
- Alidousty, C.; Duerbaum, N.; Wagener-Ryczek, S.; Baar, T.; Martelotto, L.G.; Heydt, C.; Siemanowski, J.; Holz, B.; Binot, E.; Fassunke, J.; et al. Prevalence and potential biological role of TERT amplifications in ALK translocated adenocarcinoma of the lung. Histopathology 2021, 78, 578-585, doi:10.1111/his.14256.
- Kron, A.; Alidousty, C.; Scheffler, M.; Merkelbach-Bruse, S.; Seidel, D.; Riedel, R.; Ihle, M.A.; Michels, S.; Nogova, L.; Fassunke, J.; et al. Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann Oncol 2018, 29, 2068-2075, doi:10.1093/annonc/mdy333.
- Noh, K.W.; Lee, M.S.; Lee, S.E.; Song, J.Y.; Shin, H.T.; Kim, Y.J.; Oh, D.Y.; Jung, K.; Sung, M.; Kim, M.; et al. Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. J Pathol 2017, 243, 307-319, doi:10.1002/path.4950.
- Noh, K.W.; Sohn, I.; Song, J.Y.; Shin, H.T.; Kim, Y.J.; Jung, K.; Sung, M.; Kim, M.; An, S.; Han, J.; et al. Integrin beta3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC. Clin Cancer Res 2018, 24, 4162-4174, doi:10.1158/1078-0432.CCR-17-3492.
| Keywords | ALK, NSCLC, Lung cancer |
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