Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Introduction: Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated... Conclusions: Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

Deep RNA sequencing revealed fusion junctional heterogeneity may predict crizotinib treatment efficacy in ALK-rearranged non-small cell lung cancer

Gene fusion variants in ALK-rearranged non-small cell lung cancer (NSCLC) may predict patient outcomes but previous results have been inconclusive. Fusion isoforms co-existing in the same tumor may affect targeted therapy efficacy but have not been investigated. Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Song Z, Lian S, Mak S, Chow MZ, Xu C, Wang W, Keung HY, Lu C, Kebede FT, Gao Y, Cheuk W, Cho WCS, Yang M, Zheng Z.

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated.
Patients with ALK-rearranged NSCLC who received crizotinib treatments were recruited. Precrizotinib tumor tissues were analyzed by the anchored multiplex polymerase chain reaction for targeted RNA sequencing. Kaplan-Meier and Cox regression were used to compare overall and progression-free survivals.
It was concluded that intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

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

Therapeutic Strategies to Overcome ALK Resistance in Cancer

Therapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. READ ARTICLE

Academic Press DOI: 10.1016/C2019-0-03295-5

Edited by: Luc Friboulet

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

More than 10 EML4-ALK variants based on the exon breakpoints in EML4 have been identified. Unlike other receptor tyrosine kinase fusion positive NSCLC such as ROS1 or RET fusion, EML4-ALK is the dominant fusion variant in ALK+ NSCLC accounting for approximately 85 % of all fusion variants in ALK+ NSCLC. Currently, eight EML4-ALK variants are generally recognized with a number (1, 2, 3a/b, 4′, 5a/b, 5′, 7, 8) with EML4-ALK variants 1 and 3 being the two most common variants accounting for 75–80 % of the total EML4-ALK variants. Preclinical, retrospective analyses of institutional databases, and global randomized phase 3 trials have demonstrated differential clinical response (overall response rate, progression-free survival) to ALK tyrosine kinase inhibitors (TKIs) between the “short” (v3 and v5) and “long” (v1, v2, v5′, v7, and v8) EML4-ALK variants. We discuss in more details how EML4-ALK variant structure influences protein stability and response to ALK TKIs. Additionally, the most recalcitrant single solvent-front mutation ALK G1202R is more prone to develop among EML4-ALK v3 following sequential use of next-generation ALK TKIs. Furthermore, TP53 mutations being the most common genomic co-alterations in ALK+ NSCLC also contribute to the heterogeneous response to ALK TKIs. Recognizing ALK+ NSCLC is not one homogeneous disease entity but comprised of different ALK fusion variants with different underlying genomic alterations in particular TP53 mutations that modulate treatment response will provide insight into the further optimization of treatment of ALK+ NSCLC patients potentially leading to improvement in survival. READ ARTICLE

Lung cancer DOI: 10.1016/j.lungcan.2021.06.012

Authors: Shannon S. Zhang, Misako Nagasaka, Viola W. Zhu, Sai-Hong Ignatius Ou

Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IV Therapeutic strategies in advanced ALK positive non-small cell lung cancer

Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IVTherapeutic strategies in advanced ALK positive non-small cell lung cancer. READ ARTICLE

Revue des Maladies Respiratoires DOI:Therapeutic strategies in advanced ALK positive non-small cell lung cancer

Authors: A. Tiotiu, Y. Billon, P. Vaillant, O. Menard, P. Hofman, C. Mascaux

Review PaperKirk SmithDecember 1, 2019ALK TKI, Therapeutic strategy, Rebiopsy, Resistance

PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor.
Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against
all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore,
PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse
survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a
variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment
of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors
because of secondary ALK kinase domain mutations and/or brain metastases. READ ARTICLE

Cell Cancer DOI: 10.1016/j.ccell.2015.05.010

Authors: Helen Y. Zou, Luc Friboulet, David P. Kodack, Lars D. Engstrom, Qiuhua Li, Melissa West, Ruth W. Tang, Hui Wang, Konstantinos Tsaparikos, Jinwei Wang, Sergei Timofeevski, Ryohei Katayama, Dac M. Dinh, Hieu Lam, Justine L. Lam, Shinji Yamazaki, Wenyue Hu, Bhushankumar Patel, Divya Bezwada, Rosa L. Frias, Eugene Lifshits, Sidra Mahmood, Justin F. Gainor, Timothy Affolter, Patrick B. Lappin, Hovhannes Gukasyan, Nathan Lee, Shibing Deng, Rakesh K. Jain, Ted W. Johnson, Alice T. Shaw, Valeria R. Fantin and Tod Smeal

Pre-ClinicalKirk SmithJuly 2, 2015lorlatinib, G1202R, PF-06463922, ALK TKI