Article
Oncology
Yonina R. Murciano-Goroff, Guilherme Harada, Alexander Drilon
Summary: CNS metastases pose a challenge to the design of trials for ALK fusion-positive lung cancer. The ASCEND-7 study of ceritinib demonstrates the feasibility of expanding CNS eligibility criteria and highlights design features that contemporary trials should incorporate.
CLINICAL CANCER RESEARCH
(2022)
Review
Oncology
Mariam Elshatlawy, Josephina Sampson, Katy Clarke, Richard Bayliss
Summary: Different variants of the EML4-ALK fusion gene in non-small cell lung cancer have different impacts on patient prognosis and metastatic risk. These variants form cellular compartments with distinct physical properties, which affect sensitivity to ALK tyrosine kinase inhibitors. The latest generation of ALK inhibitors is effective for most patients, but resistance can occur due to point mutations within the kinase domain of the EML4-ALK fusion.
MOLECULAR ONCOLOGY
(2023)
Article
Oncology
Edward S. Kim, Fabrice Barlesi, Tony Mok, Myung-Ju Ahn, Junwu Shen, Pingkuan Zhang, Sai-Hong Ignatius Ou
Summary: Anaplastic lymphoma kinase tyrosine kinase inhibitors have shown efficacy in ALK-rearranged non-small-cell lung cancer, particularly in patients resistant to alectinib or ceritinib. The ALTA-2 Phase II study aims to investigate the effectiveness and safety of brigatinib in ALK+ NSCLC patients with documented disease progression on alectinib or ceritinib treatment.
Article
Oncology
Sarang S. Talwelkar, Mikko I. Mayranpaa, Julia Schuler, Nora Linnavirta, Annabrita Hemmes, Simone Adinolfi, Matti Kankainen, Wolfgang Sommergruber, Anna-Liisa Levonen, Jari Rasanen, Aija Knuuttila, Emmy W. Verschuren, Krister Wennerberg
Summary: Treatment with ALK inhibitors improves outcome for NSCLC patients with ALK-rearranged tumors, but resistance typically develops. In this study, tumor cell cultures were generated from an ALK-rearranged tumor specimen and drug screens identified a role for PI3K beta and EGFR inhibition in enhancing ALK-inhibitor response and preventing resistance. Combinatorial treatment with ALK and PI3K beta inhibitors showed promise in targeting ALK-rearranged NSCLC.
MOLECULAR ONCOLOGY
(2023)
Article
Oncology
Sai-Hong Ignatius Ou, Makoto Nishio, Myung-Ju Ahn, Tony Mok, Fabrice Barlesi, Caicun Zhou, Enriqueta Felip, Filippo de Marinis, Sang-We Kim, Maurice Perol, Geoffrey Liu, Maria Rita Migliorino, Dong-Wan Kim, Silvia Novello, Alessandra Bearz, Pilar Garrido, Julien Mazieres, Alessandro Morabito, Huamao M. Lin, Hui Yang, Huifeng Niu, Pingkuan Zhang, Edward S. Kim
Summary: Brigatinib was found to have limited activity in patients with advanced ALK+ NSCLC who had received other ALK tyrosine kinase inhibitors. However, it showed longer progression-free survival in patients without detectable plasma ALK fusion at baseline.
JOURNAL OF THORACIC ONCOLOGY
(2022)
Article
Oncology
D. S-W. Tan, M. Thomas, D-W. Kim, S. Szpakowski, P. Urban, R. Mehra, L. Q. M. Chow, S. Sharma, B. J. Solomon, E. Felip, D. R. Camidge, J. Vansteenkiste, L. Petruzzelli, S. Pantano, A. T. Shaw
Summary: An exploratory analysis was conducted to understand the genetic determinants of response to ceritinib in ALK+ NSCLC patients. The study revealed the potential role of next-generation sequencing (NGS) in improving our understanding of response and resistance to ceritinib. It also demonstrated the efficacy of ceritinib against almost all ALK resistance mutations found in ALKi-pretreated patients.
Review
Oncology
Jaime L. Schneider, Jessica J. Lin, Alice T. Shaw
Summary: Shaw and colleagues discuss the oncogenic roles of ALK in lung cancer, targeting approaches and the mechanisms underlying acquired resistance to ALK-directed therapy. Anaplastic lymphoma kinase (ALK) is a potent oncogenic driver in lung cancer. ALK tyrosine kinase inhibitors yield significant benefit in patients with ALK fusion-positive (ALK(+)) lung cancers; yet the durability of response is limited by drug resistance. Elucidation of on-target resistance mechanisms has facilitated the development of next-generation ALK inhibitors, but overcoming ALK-independent resistance mechanisms remains a challenge. In this Review, we discuss the molecular underpinnings of acquired resistance to ALK-directed therapy and highlight new treatment approaches aimed at inducing long-term remission in ALK(+) disease.
Review
Oncology
Yue Pan, Chao Deng, Zhenhua Qiu, Chenghui Cao, Fang Wu
Summary: This review discusses the resistance mechanisms of ALK TKIs in advanced NSCLC, providing a theoretical basis and research ideas for solving the problem of ALK drug resistance.
FRONTIERS IN ONCOLOGY
(2021)
Review
Oncology
Wen Zhou, Lu-Da Yan, Zhi-Qiong Yu, Na Li, Yong-Hua Yang, Meng Wang, Yuan-Yuan Chen, Meng-Xia Mao, Xiao-Chun Peng, Jun Cai
Summary: ALK inhibitors have shown efficacy in treating ALK-positive NSCLC, but resistance development remains a challenge. The high cost of targeted inhibitors and potential for increased resistance to combination therapy are important issues to address. STK11 mutation may serve as a biomarker for immunotherapy in NSCLC. This review summarizes the role of STK11 in ALK-positive NSCLC and provides an overview of treatment and drug resistance studies.
Article
Oncology
Keiko Tanimura, Tadaaki Yamada, Koutaroh Okada, Kunihiro Nakai, Mano Horinaka, Yuki Katayama, Kenji Morimoto, Yuri Ogura, Takayuki Takeda, Shinsuke Shiotsu, Kosuke Ichikawa, Satoshi Watanabe, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Hirokazu Taniguchi, Kazue Yoneda, Satoaki Matoba, Toshiyuki Sakai, Hisanori Uehara, Seiji Yano, Tetsuro Kusaba, Ryohei Katayama, Koichi Takayama
Summary: This study elucidates the pivotal role of HER3 activation in the emergence of drug-tolerant cells in ALK-rearranged lung cancer, and finds that inhibiting HER3 signals combined with ALK-TKI treatment dramatically improves outcomes in ALK-rearranged lung cancer with mesenchymal features.
NPJ PRECISION ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mareike Berlak, Elizabeth Tucker, Mathurin Dorel, Annika Winkler, Aleixandria McGearey, Elias Rodriguez-Fos, Barbara Martins da Costa, Karen Barker, Elicia Fyle, Elizabeth Calton, Selma Eising, Kim Ober, Deborah Hughes, Eleni Koutroumanidou, Paul Carter, Reda Stankunaite, Paula Proszek, Neha Jain, Carolina Rosswog, Heathcliff Dorado-Garcia, Jan Jasper Molenaar, Mike Hubank, Giuseppe Barone, John Anderson, Peter Lang, Hedwig Elisabeth Deubzer, Annette Kuenkele, Matthias Fischer, Angelika Eggert, Charlotte Kloft, Anton George Henssen, Michael Boettcher, Falk Hertwig, Nils Bluthgen, Louis Chesler, Johannes Hubertus Schulte
Summary: The study identified NF1 loss and activating RAS mutations as the resistance mechanisms to ALK inhibitors in neuroblastoma. Interestingly, NF1 loss also rendered neuroblastoma cells hypersensitive to MEK inhibition.
Article
Multidisciplinary Sciences
Anna M. Schlafli, Igor Tokarchuk, Sarah Parejo, Susanne Jutzi, Sabina Berezowska, Nikolai Engedal, Mario P. Tschan
Summary: The study shows that ALK inhibition induces LC3B-independent macroautophagic flux in EML4-ALK(+) cells to support cancer cell survival and clonogenic growth.
SCIENTIFIC REPORTS
(2021)
Article
Oncology
Daisuke Kawauchi, Masamichi Takahashi, Kaishi Satomi, Shun Yamamuro, Tatsuya Kobayashi, Eita Uchida, Mai Honda-Kitahara, Yoshitaka Narita, Yasuo Iwadate, Koichi Ichimura, Arata Tomiyama
Summary: The study found that second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death in human GBM cell lines expressing low ALK levels and showed antitumor activity, suggesting that they could serve as potent therapeutic strategies against GBM.
Article
Oncology
Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Shinsaku Tokuda, Kenji Morimoto, Soichi Hirai, Yohei Matsui, Ryota Nakamura, Masaki Ishida, Hayato Kawachi, Kazue Yoneda, Kazutaka Hosoya, Takahiro Tsuji, Hiroaki Ozasa, Akihiro Yoshimura, Masahiro Iwasaku, Young Hak Kim, Mano Horinaka, Toshiyuki Sakai, Takahiro Utsumi, Shinsuke Shiotsu, Takayuki Takeda, Ryohei Katayama, Koichi Takayama
Summary: In this study, it was found that epidermal growth factor receptor (EGFR) signaling is involved in adaptive resistance to lorlatinib in ALK-rearranged NSCLC. EGFR inhibition enhanced ALK inhibition-induced apoptosis and halted the proliferation of ALK-rearranged lung cancer cells. Combination therapy with EGFR inhibitor and lorlatinib significantly suppressed tumor regrowth after cessation of treatment. This study provides new insights into tumor evolution and the development of combined therapeutic strategies for ALK-rearranged lung cancer.
NPJ PRECISION ONCOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Zhonglei Wang, Liyan Yang, Yake Li, Shaohua Song, Juan Qu, Rui He, Shanshan Ren, Peiwei Gong
Summary: A novel nano-system has been developed for the treatment of ALK/EGFR dual-mutant NSCLC. This nano-system addresses the concerns of low drug loading and inefficient drug permeability, providing a foundation for the development of GSH-sensitive nanoparticles for improved drug delivery.
NEW JOURNAL OF CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Ray Sagawa, Seiji Sakata, Bo Gong, Yosuke Seto, Ai Takemoto, Satoshi Takagi, Hironori Ninomiya, Noriko Yanagitani, Masayuki Nakao, Mingyon Mun, Ken Uchibori, Makoto Nishio, Yasunari Miyazaki, Yuichi Shiraishi, Seishi Ogawa, Keisuke Kataoka, Naoya Fujita, Kengo Takeuchi, Ryohei Katayama
Summary: Immune checkpoint therapy targeting the PD-1/PD-L1 axis is a potentially novel development in anticancer therapy. However, there are still some problems, including low response rate, resistance against immune checkpoint blockades, and the lack of reliable biomarkers. This study shows that a splicing variant of PD-L1, PD-L1-vInt4, acts as a decoy in anti-PD-L1 antibody treatment, contributing to the resistance of cancer to therapy.
Article
Oncology
Keiko Tanimura, Tadaaki Yamada, Koutaroh Okada, Kunihiro Nakai, Mano Horinaka, Yuki Katayama, Kenji Morimoto, Yuri Ogura, Takayuki Takeda, Shinsuke Shiotsu, Kosuke Ichikawa, Satoshi Watanabe, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Hirokazu Taniguchi, Kazue Yoneda, Satoaki Matoba, Toshiyuki Sakai, Hisanori Uehara, Seiji Yano, Tetsuro Kusaba, Ryohei Katayama, Koichi Takayama
Summary: This study elucidates the pivotal role of HER3 activation in the emergence of drug-tolerant cells in ALK-rearranged lung cancer, and finds that inhibiting HER3 signals combined with ALK-TKI treatment dramatically improves outcomes in ALK-rearranged lung cancer with mesenchymal features.
NPJ PRECISION ONCOLOGY
(2022)
Article
Oncology
Yuki Shimizu, Koutaroh Okada, Jun Adachi, Yuichi Abe, Ryohei Narumi, Ken Uchibori, Noriko Yanagitani, Sumie Koike, Satoshi Takagi, Makoto Nishio, Naoya Fujita, Ryohei Katayama
Summary: This study found that glycogen synthase kinase 3 (GSK3) plays a crucial role in both intermediate and acquired resistance to lorlatinib in ALK-positive NSCLC. Inhibiting GSK3 can suppress the growth of resistant cells and make other resistant cells sensitive to lorlatinib.
NPJ PRECISION ONCOLOGY
(2022)
Article
Oncology
Yuki Shimizu, Kohei Maruyama, Mai Suzuki, Hiroshi Kawachi, Siew-Kee Low, Tomoko Oh-hara, Kengo Takeuchi, Naoya Fujita, Satoshi Nagayama, Ryohei Katayama
Summary: This study found that BRAF splicing variants activate the RAF/MEK/ERK pathway in BRAF V600E mutation-positive colorectal neuroendocrine carcinomas (CRC-NECs) and contribute to resistance against BRAF inhibitors. MEK or ERK may be potential therapeutic targets to overcome BRAF resistance in CRC-NECs.
Article
Oncology
Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Shinsaku Tokuda, Kenji Morimoto, Soichi Hirai, Yohei Matsui, Ryota Nakamura, Masaki Ishida, Hayato Kawachi, Kazue Yoneda, Kazutaka Hosoya, Takahiro Tsuji, Hiroaki Ozasa, Akihiro Yoshimura, Masahiro Iwasaku, Young Hak Kim, Mano Horinaka, Toshiyuki Sakai, Takahiro Utsumi, Shinsuke Shiotsu, Takayuki Takeda, Ryohei Katayama, Koichi Takayama
Summary: In this study, it was found that epidermal growth factor receptor (EGFR) signaling is involved in adaptive resistance to lorlatinib in ALK-rearranged NSCLC. EGFR inhibition enhanced ALK inhibition-induced apoptosis and halted the proliferation of ALK-rearranged lung cancer cells. Combination therapy with EGFR inhibitor and lorlatinib significantly suppressed tumor regrowth after cessation of treatment. This study provides new insights into tumor evolution and the development of combined therapeutic strategies for ALK-rearranged lung cancer.
NPJ PRECISION ONCOLOGY
(2023)
Article
Oncology
Mizuki Haraguchi, Kazuma Kiyotani, Tomohiro Tate, Seiji Sakata, Ray Sagawa, Satoshi Takagi, Satoshi Nagayama, Kengo Takeuchi, Kazuhisa Takahashi, Ryohei Katayama
Summary: Immune checkpoint inhibitors (ICIs) have shown significant clinical responses and improved overall survival for various cancers. However, response to ICI therapy varies among patients. This study established a mouse model to better understand the host immune response to tumors and the role of T cells in ICI therapy. The study also identified shared T cell receptors (TCR) in colorectal cancer (CRC) patients. The results suggest that memory T cells play a crucial role in the immune response to tumors and the established model has potential for studying systemic memory T cell behavior.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2023)
Meeting Abstract
Oncology
Yuki Takahashi, Yuki Shimizu, Shiro Kitano, Satoshi Nagayama, Ryohei Katayama, Naoya Fujita
Meeting Abstract
Oncology
Keiko Tanimura, Tadaaki Yamada, Kazue Yoneda, Mano Horinaka, Toshiyuki Sakai, Hisanori Uehara, Seiji Yano, Ryohei Katayama
Meeting Abstract
Oncology
Ryohei Katayama, Naoya Fujita
Meeting Abstract
Oncology
Kohei Maruyama, Yuki Shimizu, Mai Suzuki, Tomoko Ohhara, Naoya Fujita, Satoshi Nagayama, Ryohei Katayama
Meeting Abstract
Oncology
Hayato Mizuta, Ai Takemoto, Satoshi Takagi, Siro Simizu, Makoto Nishio, Naoya Fujita, Ryohei Katayama
Meeting Abstract
Oncology
Rii Morimura, Shiro Kitano, Ryohei Katayama, Naoya Fujita, Yoshihiko Hirohashi, Toshihiko Torigoe
Meeting Abstract
Oncology
Tomoko Ohhara, Naoya Fujita, Makoto Nishio, Ryohei Katayama
Meeting Abstract
Oncology
Mingjue Chen, Tetsuo Mashima, Yukiko Muramatsu, Yuki Shimizu, Satoshi Nagayama, Ryohei Katayama, Hiroyuki Seimiya