Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on-target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off-target’ mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies. READ ARTICLE

Nat Rev Clin Oncol DOI:10.1038/s41571-022-00639-9

Authors: Cooper, A.J., Sequist, L.V. & Lin, J.J.

Driver and novel genes correlated with metastasis of non-small cell lung cancer: A comprehensive analysis

Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, E..... READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2021.153551

Authors: Yongfeng Wu, Heng Ni, Dexin Yang, Yuequn Niu, Kelie Chen, Jinming Xu, Fang Wang, Song Tang, Yu Shi, Honghe Zhang, Jian Hu, Dajing Xia, Yihua Wu

Pre-Clinical, group4Kirk SmithJuly 10, 2021Metastasis, Mutation, SMARCA1, EDNRB

EML4–ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7

EML4–ALK is an oncogenic fusion present in ∼5% of non-small cell lung cancers. However, alternative breakpoints in the EML4 gene lead to distinct variants of EML4–ALK with different patient outcomes. Here, we show that, in cell models, EML4–ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. EML4–ALK V3 also recruits the NEK9 and NEK7 kinases to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but does not require ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4–ALK patients. Hence, we propose that EML4–ALK V3 promotes microtubule stabilization through NEK9 and NEK7, leading to..... READ ARTICLE

Journal of Cell Science DOI:10.1242/jcs.241505

Authors: Laura O'Regan, Giancarlo Barone, Rozita Adib, Chang Gok Woo, Hui Jeong Jeong, Emily L. Richardson, Mark W. Richards, Patricia A. J. Muller, Spencer J. Collis, Dean A. Fennell, Jene Choi, Richard Bayliss, Andrew M. Fry

Pre-ClinicalKirk SmithMay 11, 2020EML4–ALK, EML4, NEK9, NEK7, NSCLC, Microtubules, Cell migration, Metastasis, versions

Two Cases of Krukenberg Tumors from ALK-Rearranged Lung Adenocarcinoma: An Uncommon Site of Metastasis

Approximately 5% of all NSCLCs harbor ALK receptor tyrosine kinase gene (ALK) rearrangements.1 ALK-rearranged NSCLC is more commonly associated with younger individuals and those without a smoking history. The most common ALK rearrangement is a fusion between the ALK gene and gene echinoderm microtubule associated protein like 4 gene (EML4).1 Several drugs targeting ALK-rearranged NSCLC are currently available. Unfortunately, almost all ALK-positive NSCLCs will eventually progress during treatment with ALK inhibitors. This is mainly due to ALK point mutations, most commonly a L1196M mutation and the G1269A mutation, although several others have been identified.2 NSCLC tends to spread to the bones, brain, liver, lungs, and adrenal glands. ALK-positive NSCLCs have an increased tendency to metastasize to the pericardium, pleura, and liver compared with other NSCLCs.3 Rarely, tumors can metastasize to the ovaries; such tumors are known as Krukenberg tumors. Typically, Krukenberg tumors ori..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.05.028

Authors: John (Jack) Ogden, Hao Xie, Randolph S. Marks, Konstantinos Leventakos

EditorialKirk SmithOctober 1, 2019Krukenberg Tumors, ALK-Rearranged, Lung Adenocarcinoma, Metastasis

Computed Tomography Imaging Characteristics of Non–Small-Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements: A Systematic Review and Meta-Analysis

Background: Young patients are rarely diagnosed with non-small cell lung cancer (NSCLC), and little is known about its predisposing genomic alterations and survival. Conclusions: Younger patients with NSCLC had a higher frequency of gene fusions than older patients and had a trend of worse OS. READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2019.03.39

Authors: Shifeng Yang, Zhengbo Song, Guoping Cheng