&lt;p&gt;Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions&lt;/p&gt;

Ackermann, Christoph; Stock, Gustavo Trautman; Tay, Rebecca; Dawod, Mohammed; Gomes, Fábio; Califano, Raffaele

doi:10.2147/ott.s171665

Cited by 34 publications

(23 citation statements)

References 59 publications

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“…More recently, novel selective RET inhibitors (BLU-667, LOXO-292 and RXDX-105) have been investigated in early phase clinical trials in NSCLC, showing promising efficacy with a manageable toxicity profile [110] .…”

Section: Anti-ret Drugsmentioning

confidence: 99%

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

Nigro¹,

Rusmini²,

Ceccherini³

2019

CDR

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Initiation, progression, outcome and sensibility to therapies in breast cancer (BC), the most frequent cancer in women, are driven by somatic and germline mutations. Although the effectiveness of hormonal therapies is well-founded, it is prescribed for cancers which express steroid hormone receptors, such as estrogen receptor (ER). RET is a protooncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands (GDNF, neurturin, artemin or persephin) and one of its coreceptors (Gfrα1-4). Loss-of-function mutations in RET are responsible for Hirschsprung disease, while gain-of-function mutations for multiple endocrine neoplasia type 2. In addition, deregulation of its intracellular signaling, due to mutations, gene rearrangements, overexpression or transcriptional upregulation, can cause several neuroendocrine and epithelial tumors. In BC, amplification of receptor tyrosine kinases, such as ERBB2, EGFR, IGFR and FGFR1, and/or their upregulation contribute to cancer initiation and progression. RET can also have an important role in BC, but only in the subset of ER-positive (ER+) tumors, where it is found overexpressed. Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+ BC, improving treatment outcome and preventing tumor-related events. Thus, here, we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

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Section: Anti-ret Drugsmentioning

confidence: 99%

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

Nigro¹,

Rusmini²,

Ceccherini³

2019

CDR

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“…The advantage of a molecular FFT is that it applies to all molecular targets and while NCCN guidelines and other pathways have incorporated a few molecular targets such as EGFR, ALK, ROS1, and BRAF, they do not include MET, RET, NTRK or KRAS, for which therapies are quickly emerging and showing immense benefits to patients [ 48 , 49 , 50 , 51 , 52 ]. Our FFT would benefit community practice as it would incorporate those molecular targets into the decision-making strategy regardless of whether the therapy is FDA-approved or if it is in a clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting—Role of Academic and Hybrid Modeling

Salgia

Mambetsariev

Tan

et al. 2020

JCM

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Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy.

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“…Notably, these patients suffered from high-grade toxicity mainly induced by anti-VEGFR kinase activity. Therefore, selective RET inhibitors such as BLU-667, LOXO-292, and RXDX-105 have been recently investigated in early phase clinical trials and showed promising efficacy with a manageable toxicity profile [ 66 ].…”

Section: Novel Compoundsmentioning

confidence: 99%

Novel Multitarget Therapies for Lung Cancer and Respiratory Disease

2020

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In recent years, multitarget drugs for neurological diseases such as Alzheimer’s disease have been developed and well researched. Many studies have revealed that multitarget drugs are also useful for lung cancer and respiratory diseases. Pemetrexed is a multitargeted antifolate with strong antitumor activity against mesothelioma and lung adenocarcinoma. Crizotinib is an ATP-competitive tyrosine kinase inhibitor that targets c-MET, ROS1, and ALK. Alectinib is known as an ALK inhibitor but also targets LTK, CHEK2, FLT3, PHKG2, and RET. Sorafenib is a tyrosine kinase inhibitor that targets RAF kinase, KIT, VEGFR, PDGFR1β, FLT3, and RET. Nintedanib is a multiple tyrosine kinase inhibitor that targets FGFR, PDGFR, and VEGFR. In this review, we summarize the mechanisms of action of multitarget therapies and report the results of the latest clinical trials.

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<p>Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions</p>

Cited by 34 publications

References 59 publications

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting—Role of Academic and Hybrid Modeling

Novel Multitarget Therapies for Lung Cancer and Respiratory Disease

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