TRKing Down an Old Oncogene in a New Era of Targeted Therapy

Vaishnavi, Aria; Le, Anh‐Tuan; Doebele, Robert C.

doi:10.1158/2159-8290.cd-14-0765

Cited by 561 publications

(516 citation statements)

References 90 publications

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“…No TRKA inhibitors were explored in clinical trials with the possible exception of lestaurtinib (CEP-701), a staurosporine-derivative multikinase inhibitor that was investigated in clinical settings with reported TRKA overexpression, without evidence of efficacy (7,38). However, recent studies that have identified recurring oncogenic NTRK1 rearrangements in subsets of NSCLC and colorectal carcinoma patients (11,12), as well as other studies suggesting a potential role of activated TRKA in other tumor types, including glioblastoma and Spitz melanoma (14)(15)(16)39), have created much renewed interest in the identification and clinical investigation of effective TRKA inhibitors (13). In a rapidly evolving scenario, these findings indicate that TRKA inhibition may represent an innovative opportunity for the therapy of selected patients whose tumors harbor NTRK1 gene rearrangements and this has supported the enrollment of TRKA-positive patients in ongoing clinical trials of entrectinib.…”

Section: Discussionmentioning

confidence: 99%

“…Although an accurate estimation of the frequency of translocation events involving TRKA in either NSCLC or colorectal carcinoma is not yet available due to the low number of cases reported to date, these findings pave the way for targeted therapy with selective TRKA inhibitors in these patients (13). Moreover, in a rapidly evolving landscape, large-scale sequencing efforts have led to identification of additional chromosomal rearrangements involving NTRK1 as well as NTRK2 and NTRK3, the genes which respectively encode the TRKA, TRKB, and TRKC proteins, in further tumor types (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

265

191

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Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

265

191

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“…6,[15][16][17] The NTRK2 fusion gene was first identified in pilocytic astrocytoma, with recent reports of additional fusions including QKI-NTRK2, NACC2-NTRK2, VCL-NTRK2, AGBL4-NTRK2, TRIM24-NTRK2, PAN3-NTRK2, AFAP1-NTRK2, SQSTM1-NTRK2, NAV1-NTRK2, and SLMAP-NTRK2. 6,[15][16][17]41,42 The mechanism of action of these fusion proteins in human gliomagenesis, progression, and drug resistance remains poorly understood. In this study we performed a systematic screen of TK-TELs, which suggested that activated TrkB could transform Ink4a −/− /Arf −/− astrocytes in vivo via upregulation of pSTAT3 signaling and Ccl2 production.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine receptor kinase B is a drug target in astrocytomas

Xie

Ramkissoon

et al. 2016

Neuro-Oncology

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Background. Astrocytomas are the most common primary human brain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and lowgrade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type. Methods. To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a −/− /Arf −/− astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas. Results. Activated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with human astrocytoma transformed Ink4a −/− /Arf −/− astrocytes, and this process was also mediated via STAT3 signaling. Conclusions. Our findings provide evidence that constitutively activated NTRK2 alleles, notably the human tumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytoma patients defined by QKI-NTRK2 fusion. Key words astrocytoma | CCL2 | NTRK2 | STAT3 | QKI-NTRK2

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“…Genomic rearrangement is the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation through activation of MAPK and AKT downstream pathways ( 1 ). Rearrangements of the NTRK1 , NTRK2 , and NTRK3 genes occur across different tumors, including colorectal cancers ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Russo

Misale

Ge³

et al. 2016

Cancer Discovery

271

272

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Entrectinib is a fi rst-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profi ling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1 , p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confi rmed that either mutation renders the TRKA kinase insensitive to entrectinib. These fi ndings can be immediately exploited to design next-generation TRKA inhibitors. SIGNIFICANCE:We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identifi cation of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the fi rst time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1);[36][37][38][39][40][41][42][43][44]

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TRKing Down an Old Oncogene in a New Era of Targeted Therapy

Cited by 561 publications

References 90 publications

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

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

Tyrosine receptor kinase B is a drug target in astrocytomas

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

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