Studies in mouse models support an essential role of lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transition (AST) in the development of drug resistance. Recent observations in the clinic further suggest that this type of histological transition may be responsible for resistance to tyrosine kinase inhibitor (TKI) therapy and chemotherapy in relapsed EGFR-mutant lung ADC patients. Here we summarize the current understanding of AST and drug resistance. READ ARTICLE
Trends in Cancer DOI:10.1016/j.trecan.2016.08.002
Authors: Shenda Hou, Xiangkun Han, Hongbin Ji
... We report a case of LCNEC harboring a novel PLB1-ALK rearrangement sensitive to crizotinib by next-generation sequencing (NGS). The patient’s disease responded to crizotinib for > 5 months... NGS demonstrates an additional advantage of being able to concurrently detect different mutations in genetic testing and plays an important role in detecting ALK-rearranged non–small-cell lung cancer. Screening for ALK rearrangement by NGS in patients with LCNEC may help in selecting potential candidates for targeted therapy. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.026
Authors: Shuai Wang, Xuan Wu, Jiuzhou Zhao, Haiyang Chen, Zhe Zhang, Mingyue Wang, Cong Xu, Yongsen Wang, Lili Wang, Zhen He, Qiming Wang
At J-ALEX IA, Alectinib demonstrated significantly prolonged PFS compared with Crizotinib and was well tolerated with a favorable AE profile. READ ARTICLE
Journal of Clinical Oncology DOI: 10.1200/JCO.2016.34.15_suppl.9008
Authors: Hiroshi Nokihara, Toyoaki Hida, Masashi Kondo, Young Hak Kim, Koichi Azuma, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Fumio Imamura, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Hiroshi Kuriki, Ryoichi Asabe, Tomohiro Tanaka, Tomohide Tamura
Read MoreThese results confirm the findings from PROFILE 1014 and demonstrate that first-line crizotinib significantly improves PFS and ORR vs PCC in an East Asian population with ALK+ advanced NSCLC with an acceptable safety profile. Clinical trial information: NCT01639001. READ ARTICLE
Journal of Clinical Oncology DOI: 10.1200/JCO.2016.34.15_suppl.9058
AUTHORS: Shun Lu, Tony Mok, You Lu, Jianying Zhou, Yuankai Shi, Virote Sriuranpong, James C. M. Ho, Choo Khoon Ong, Chun-Ming Tsai, Chin-Hee Chung, Keith D. Wilner, Yiyun Tang, Elizabeth Masters, Paulina Selaru, Yi-Long Wu
Read MoreBone metastases of non–small cell lung cancer (NSCLC) may present an osteolytic or osteoblastic pattern, and their occurrence during treatment qualifies as progressive disease. However, “osteoblastic responses” (the appearance of either new osteoblastic lesions or a sclerotic component within preexisting lytic lesions) have been described, particularly in epidermal growth factor receptor gene (EGFR)-addicted NSCLC READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2016.04.002
Authors: Francesco Gelsomino, Valentina Ambrosini, Barbara Melotti, Francesca Sperandi, Andrea Ardizzoni
Nucleosome positioning varies between cell types. By deep sequencing cell-free DNA (cfDNA), isolated from circulating blood plasma, we generated maps of genome-wide in vivo nucleosome occupancy and found that short cfDNA fragments harbor footprints of transcription factors. The cfDNA nucleosome occupancies correlate well with the nuclear architecture, gene structure, and expression observed in cells, suggesting that they could inform the cell type of origin. Nucleosome spacing inferred from cfDNA in healthy individuals correlates most strongly with epigenetic features of lymphoid and myeloid cells, consistent with hematopoietic cell death as the normal source of cfDNA. We build on this observation to show how nucleosome footprints can be used to infer cell types contributing to cfDNA in pathological states such as cancer. Since this strategy does not rely on genetic differences to distinguish between contributing tissues, it may enable the noninvasive monitoring of a much broader set o..... READ ARTICLE
Cell DOI:10.1016/j.cell.2015.11.050
Authors: Matthew W. Snyder, Martin Kircher, Andrew J. Hill, Riza M. Daza, Jay Shendure
Anaplastic lymphoma kinase (ALK) fusion is a common mechanism underlying pathogenesis of non-small cell lung carcinoma (NSCLC) where these rearrangements represent important diagnostic and therapeutic targets. In this study, we found a new ALK fusion gene, SEC31A-ALK, in lung carcinoma from a 53-year-old Korean man. The conjoined region in the fusion transcript was generated by the fusion of SEC31A exon 21 and ALK exon 20 by genomic rearrangement, which contributed to generation of an intact, in-frame open reading frame. SEC31A-ALK encodes a predicted fusion protein of 1,438 amino acids comprising the WD40 domain of SEC31A at the N-terminus and ALK kinase domain at the C-terminus. Fluorescence in situ hybridization studies suggested that SEC31A-ALK was generated by an unbalanced genomic rearrangement associated with loss of the 3′-end of SEC31A. This is the first report of SEC31A-ALK fusion transcript in clinical NSCLC, which could be a novel diagnostic and therapeutic target for patie..... READ ARTICLE
Cancer Research and Treatment DOI:10.4143/crt.2014.254
Authors: Ryong Nam Kim, Yoon-La Choi, Mi-Sook Lee, Maruja E. Lira, Mao Mao, Derrick Mann, Joshua Stahl, Abel Licon, So Jung Choi, Michael Van Vrancken, Joungho Han, Iwona Wlodarska and Jhingook Kim
DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as well as on factors involved in the activation of apoptosis, necrosis, autophagy and senescence. The pathways that dictate cell fate are entwined and have key roles in cancer initiation and progression. Furthermore, they determine the outcome of cancer therapy with genotoxic drugs. Understanding the molecular basis of these pathways is important not only for gaining insight into carcinogenesis, but also in promoting successful cancer therapy. In this Review, we describe key decision-making nodes in the complex interplay between cell survival and death following DNA damage. READ ARTICLE
Nature Reviews Cancer DOI: 10.1038/nrc.2015.2
Authors: Wyn P. Roos, Adam D. Thomas, Bernd Kaina
Read MoreOne strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS–mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRASWT) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK–positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes. READ ARTICLE
Nature Medicine DOI:10.1038/nm.3930
Authors: Gorjan Hrustanovic, Victor Olivas, Evangelos, Pazarentzos, Asmin Tulpule, Saurabh Asthana, Collin M. Blakely, Ross A. Okimoto, Luping Lin, Dana S. Neel, Amit Sabnis, Jennifer Flanagan, Elton Chan, Marileila, Varella-Garcia, Dara L. Aisner, Aria Vaishnavi, Sai-Hong I. Ou, Eric A. Collisson, Eiki Ichihara, Philip C. Mack, Christine M. Lovly, Niki Karachaliou, Rafael Rosell, Jonathan W. Riess, Robert C. Doebele & Trever G. Bivona
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
Systemic anaplastic large cell lymphoma (ALCL) is an aggressive CD30+ non-Hodgkin lymphoma. Anaplastic lymphoma kinase–positive (ALK+) ALCL is associated with the NPM-ALK t(2;5) translocation, which is highly correlated with the identification of the ALK protein by immunohistochemistry. ALK+ ALCL typically occurs in younger patients and has a more favorable prognosis with 5-year survival rates of 70% to 90% in comparison with 40% to 60% for ALK-negative (ALK−) ALCL. Studies support young age as a strong component of the favorable prognosis of ALK+ ALCL. Until recently, no recurrent translocations were identified in ALK− ALCL. However, emerging data now highlight that ALK− ALCL is genetically and clinically heterogeneous with a subset having either a DUSP22 translocation and a survival rate similar to ALK+ ALCL or a less common P63 translocation, the latter associated with an aggressive course. Anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment choice for systemic ALCL, but in many patients with ALK− ALCL, it is ineffective, and thus it is often followed by consolidative autologous stem cell transplantation. However, selection of appropriate patients for intensified therapy remains challenging, particularly in light of genetic and clinical heterogeneity in addition to the emergence of new, effective therapies. The antibody drug conjugate brentuximab vedotin is associated with a high response rate (86%) and durable remissions in relapsed/refractory ALCL and is under investigation in the first-line setting. In the future, combining clinical and genetic biomarkers may aid in risk stratification and help guide initial patient management. READ ARTICLE
Blood DOI: 10.1182/blood-2014-10-567461
Authors: Greg Hapgood, Kerry J. Savage
Read MoreThe prokaryotic type II CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated 9) system is rapidly revolutionizing the field of genetic engineering, allowing researchers to alter the genomes of a large range of organisms with relative ease. Experimental approaches based on this versatile technology have the potential to transform the field of cancer genetics. Here, we review current approaches for functional studies of cancer genes that are based on CRISPR–Cas, with emphasis on their applicability for the development of next-generation models of human cancer. READ ARTICLE
Nature Reviews Cancer DOI: 10.1038/nrc3950
Authors: Francisco J. Sánchez-Rivera, Tyler Jacks
Read MoreOur findings that both EML4–ALK and mutant EGFR upregulate PD-L1 by activating PI3K–AKT and MEK–ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression READ ARTICLE
Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-15-0016
Authors: Keiichi Ota, Koichi Azuma, Akihiko Kawahara, Satoshi Hattori, Eiji Iwama, Junko Tanizaki,Taishi Harada, Koichiro Matsumoto, Koichi Takayama, Shinzo Takamori, Masayoshi Kage, Tomoaki Hoshino, Yoichi Nakanishi and Isamu Okamoto
Read MoreWith therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4–8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions. READ ARTICLE
European Respiratory Journal DOI: 10.1183/09031936.00236414
Authors: Boris Duchemann, Luc Friboulet, Benjamin Besse
Read MoreAlectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. READ ARTICLE
Lancet, Oncology DOI:10.1016/S1470-2045(14)70362-6
Authors: Shirish M Gadgeel, Leena Gandhi, Gregory J Riely, Alberto A Chiappori, Howard L West, Michele C Azada, Peter N Morcos, Ruey-Min Lee, Linta Garcia, Li Yu, Frederic Boisserie, Laura Di Laurenzio, Sophie Golding, Jotaro Sato, Shumpei Yokoyama, Tomohiro Tanaka, Sai-Hong Ignatius Ou
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity. READ ARTICLE
Journal of Medicinal Chemistry DOI:10.1021/jm500261q
Authors: Ted W. Johnson, Paul F. Richardson, Simon Bailey, Alexei Brooun, Benjamin J. Burke, Michael R. Collins, J. Jean Cui, Judith G. Deal, Ya-Li Deng, Dac Dinh, Lars D. Engstrom, Mingying He, Jacqui Hoffman, Robert L. Hoffman, Qinhua Huang, Robert S. Kania, John C. Kath, Hieu Lam, Justine L. Lam, Phuong T. Le, Laura Lingardo, Wei Liu, Michele McTigue, Cynthia L. Palmer, Neal W. Sach, Tod Smeal, Graham L. Smith, Albert E. Stewart, Sergei Timofeevski, Huichun Zhu, Jinjiang Zhu, Helen Y. Zou, and Martin P. Edwards
In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non–small-cell lung cancers. ALK-positive cancers are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011. Although crizotinib induces remissions and extends the lives of patients, cures are not achieved as resistance to therapy develops. In this review, we will discuss the history of this field, current diagnostic and treatment practices, and future challenges and opportunities to advance outcomes for patients with ALK-positive lung cancers. READ ARTICLE
Journal of Clinical Oncology DOI: 10.1200/JCO.2012.44.5353
Authors: Alice T. Shaw, Jeffrey A. Engelman
Read MoreThrough an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion–positive and 13 ROS1-fusion–positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion–positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥50 years, male sex, high pathological stage and negative kinase-fusion status. READ ARTICLE
Nature Medicine DOI: 10.1038/nm.2658
Authors: Kengo Takeuchi, Manabu Soda, Yuki Togashi, Ritsuro Suzuki, Seiji Sakata, Satoko Hatano, Reimi Asaka, Wakako Hamanaka, Hironori Ninomiya, Hirofumi Uehara, Young Lim Choi, Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Hiroyuki Mano, Yuichi Ishikawa
Read MoreThe MTD of PF is 250 mg BID. The major AEs were fatigue or GI-related, and all AEs were manageable and reversible. There was no evidence of non-linear PK at PF doses >100 QD. Treatment with PF-02341066 resulted in promising clinical activity against tumors carrying activating ALK gene rearrangements. Further study of PF in pts with ALK-dependent tumors is warranted. READ ARTICLE
Journal of Clinical Oncology
Authors: E. L. Kwak, D. R. Camidge, J. Clark, G. I. Shapiro, R. G. Maki, M. J. RatainB. Solomon, Y. Bang, S. Ou, R. Salgia
Read MoreImprovement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4–ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC...... READ ARTICLE
Nature DOI:10.1038/nature05945
Authors: Manabu Soda, Young Lim Choi, Munehiro Enomoto, Shuji Takada, Yoshihiro Yamashita, Shunpei Ishikawa, Shin-ichiro Fujiwara, Hideki Watanabe, Kentaro Kurashina, Hisashi Hatanaka, Masashi Bando, Shoji Ohno, Yuichi Ishikawa, Hiroyuki Aburatani, Toshiro Niki, Yasunori Sohara, Yukihiko Sugiyama & Hiroyuki Mano