Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini, Elena; Menichincheri, Maria; Banfi, Patrizia; Bosotti, Roberta; Ponti, Cristina; Pulci, Romana; Ballinari, Dario; Ciomei, Marina; Texidó, Gemma; Degrassi, Anna; Avanzi, Nilla; Amboldi, Nadia; Saccardo, Maria Beatrice; Casero, Daniele; Orsini, Paolo; Bandiera, Tiziano; Mologni, Luca; Anderson, David W.; Ge, Wei; Harris, Jason; Vernier, Jean‐Michel; Li, Gang; Felder, E.; Donati, Daniele; Isacchi, Antonella; Pesenti, Enrico; Magnaghi, Paola; Galvani, Arturo

doi:10.1158/1535-7163.mct-15-0758

Cited by 247 publications

(192 citation statements)

References 43 publications

(56 reference statements)

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“…Entrectinib is an oral inhibitor with low nanomolar potency against ALK, ROS1, and TRK kinases in enzymatic assays (85), and is able to effectively penetrate the blood-brain barrier (86). Its cellular IC 50 against ROS1 in Ba/F3 models is ~5 nM (86).…”

Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

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Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

199

201

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ROS1 is a validated therapeutic target in non-small cell lung cancer (NSCLC). In a phase I study, the multi-targeted MET/ALK/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs, and consequently gained approval by the United States Food and Drug Administration as well as the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors (TKIs) are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.

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Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

“…Its cellular IC 50 against ROS1 in Ba/F3 models is ~5 nM (86). Notably, entrectinib has failed to demonstrate preclinical activity against the ROS1 L2026M or G2032R resistance mutations (81), suggesting it likely has little role in treating crizotinib-resistant ROS1 -rearranged NSCLC.…”

Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

199

201

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“…Given these findings, a primary breast cancer was suspected and she underwent a right central partial mastecto- pression of this ETV6-NTRK3 gene leads to formation of a chimeric tyrosine kinase that activates the Ras-MAPK and inositol-3'-kinase Akt pathways, which are noted to be the first event in the oncogenesis of SBC [11,12]. Furthermore, it was shown that a retroviral transfer of the same fusion gene induced SBC in mice [6].…”

Section: Discussionmentioning

confidence: 99%

Secretory Carcinoma of the Breast: An Elusive Presentation of This Rare Pathology

Joseph¹,

Morgani²,

Heimann³

et al. 2017

Int J Oncol Res

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terial, samples are strongly S-100 protein reactive. Secretory breast carcinoma is driven by the fusion gene ETV6-NTRK3 that results from a balanced translocation t (12; 15) [6].Fortunately for most diagnosed with SBC, the course is indolent even in the setting of nodal metastasis, which is present in 15-35% cases at presentation [2,3,7]. Although distant metastasis is very rare, local recurrence is described, recurring as far as 16 years after treatment [8]. At present the primary treatment remains surgical. Case ReportA 75-year-old female presented to our clinic with complaint of new onset right nipple pain and swelling for 4 weeks. Family history was significant for breast cancer in a maternal and a paternal first cousin, as well as a maternal aunt who succumbed to her disease at age 50. The initial physical exam revealed a tender, erythematous, enlarged right nipple, but no palpable masses. The initial impression was mastitis, and she was started on azithromycin. A diagnostic mammogram showed asymmetry of the right nipple compared to the left ( Figure 1), however, ultrasound at that time was unremarkable. Her symptoms did not improve with antibiotics.A repeat targeted ultrasound of this area revealed an abnormal right nipple complex (Figure 2). She was then assessed by a breast surgeon, and the exam at that time revealed a firm, tender, erythematous mass of the superior aspect of the right nipple, and a palpable right axillary lymph node. Ultrasound-guided fine needle aspiration biopsy of the axillary node was consistent with metastatic adenocarcinoma. The tumor stained positive AbstractSince first being noted in the literature in 1966, Secretory Breast Carcinoma (SBC) continues to be better defined in terms of its clinical, histologic, and genetic features. However, its unique presentation can elude seasoned practitioners from making a clinical diagnosis. Furthermore, there is neither consensus nor guidelines as to the optimal treatment approach for SBC. We are presenting this case report and literature review to raise awareness about SBC by demonstrating how uniquely this pathology can present itself, to summarize the current literature, and to present our specific approach to this rare cancer.

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“…Patients with NTRK1 -rearranged NSCLC are particularly young and predominantly never-smokers. The pan-TRK inhibitors entrectinib and LOXO-101 are subject to clinical development and show promising activity in pre-clinical models and early clinical setting [68,99,102,103,104]. …”

Section: New Targets In Sclc and Nsclcmentioning

confidence: 99%

Stratified Treatment in Lung Cancer

Michels

Wolf²

2016

Oncol Res Treat

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Even though great efforts have been made to improve chemotherapy-based treatment approaches for lung cancer, the prognosis of patients with advanced and metastasized disease remains particularly poor. In recent years, a growing number of genetic aberrations driving lung cancer have been identified. Targeted inhibition of some of these aberrations, most prominently mutated EGFR and ALK, by tyrosine kinase inhibitors has dramatically increased efficacy and tolerability of systemic lung cancer treatment in subsets of patients. However, the duration of response is limited due to the acquisition of molecular mechanisms of resistance to targeted treatment. Modern next-generation inhibitors aim to break resistance. A deep understanding of the mechanisms of treatment failure is imperative to the development of new approaches. In this review, we focus on the current status of stratified therapy in lung cancer and highlight new, potentially promising treatment approaches.

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Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Cited by 247 publications

References 43 publications

Recent Advances in Targeting ROS1 in Lung Cancer

Recent Advances in Targeting ROS1 in Lung Cancer

Secretory Carcinoma of the Breast: An Elusive Presentation of This Rare Pathology

Stratified Treatment in Lung Cancer

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