Tumor Shrinkage With Combination of Alectinib and Trastuzumab in a Patient With ALK-Rearranged Non–small Cell Lung Cancer Harboring HER2-Amplification...

Clinical Practice Points:
• HER2 amplification is an acquired resistance mechanism in ALK-rearranged non–small cell lung cancer.
• FISH analysis revealed a minor subclone of HER2-amplified cells before becoming the dominant resistance mechanism.
• Combination of HER2 and ALK therapies may be an effective treatment approach for ALK-rearranged NSCLC with acquired HER2 amplification. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.06.012

Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter, D. Ross Camidge

Case StudyKirk SmithMarch 1, 2022ALK, HER2, Lung cancer, Acquired resistance, Trastuzumab

Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC. READ ARTICLE

Cancers DOI: 10.3390/cancers13040699

Authors: Elisabeth Smolle, Valentin Taucher, Joerg Lindenmann, Philipp J. Jost, Martin Pichler

Novel Resistance Mechanisms Including L1196Q, P1094H, and R1248_D1249 Insertion in Three Patients With NSCLC After ALK Tyrosine Kinase Inhibitor Treatment

"Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs.The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field." READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2020.09.023

Authors: Furuta H, Araki M, Masago K, Sagae Y, Fujita S, Seto K, Shimizu J, Horio Y, Sasaki E, Hosoda W, Katayama R, Okuno Y, Hida T.

Emerging EML4-ALK Variant 5 as a Concurrent Resistance Mechanism to Osimertinib in a Patient With EGFR E19del/T790M NSCLC

The management of patients with epidermal growth factor receptor (EGFR)-mutant, metastatic non–small-cell lung cancer (NSCLC) who become resistant to EGFR inhibitors remains challenging given the presence of complex and heterogeneous resistance mechanisms. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.009

Authors: Yan Yan, Guozhong Jiang, Weijie Ma, Tianhong Li, Liping Wang

Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights

While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment. READ ARTICLE

Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2020.107522

Authors: Catherine B. Meador, Aaron N. Hata

Revealing acquired resistance mechanisms of kinase-targeted drugs using an on-the-fly, function-site interaction fingerprint approach

Although kinase-targeted drugs have achieved significant clinical success, they are frequently subject to the limitations of drug resistance, which has become a primary vulnerability to targeted drug therapy. Therefore, deciphering resistance mechanisms is an important step in designing more efficacious, anti-resistant, drugs. Here we studied two FDA-approved kinase drugs: Crizotinib and Ceritinib, which are first- and second-generation anaplastic lymphoma kinase (ALK) targeted inhibitors, to unravel drug-resistance mechanisms. We used an on-the-fly, function-site interaction fingerprint (on-the-fly Fs-IFP) approach by combining binding free energy surface calculations with the Fs-IFPs. Establishing the potentials of mean force and monitoring the atomic-scale protein-ligand interactions, before and after the L1196M-induced drug resistance, revealed insights into drug-resistance/anti-resistant mechanisms. Crizotinib prefers to bind the wild type ALK kinase domain, whereas Ceritinib bind..... READ ARTICLE

Journal of Chemical Theory and Computation DOI:10.1021/acs.jctc.9b01134

Authors: Zheng Zhao, Philip E. Bourne

NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors

Background: Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. Because immunotherapy is an option for patients with drug-resistant cancers, we generated several TKI-resistant NSCLC cell lines in vitro, and then evaluated the cytotoxicity of NK92-CD16 cells to these resistant cells. Conclusion: Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. READ ARTICLE

Cytotherapy DOI:10.1016/j.jcyt.2019.03.312

Authors: HA-RAM PARK, YONG-OON AHN, TAE MIN KIM, SOYEON KIM, SEULKI KIM, YU SOO LEE, MISO KIM, BHUMSUK KEAM, DONG-WAN KIM, DAE SEOG HEO