Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Wagle, Nikhil; Grabiner, Brian C.; Allen, Eliezer M. Van; Amin‐Mansour, Ali; Taylor-Weiner, Amaro; Rosenberg, Mara; Gray, Nathanael S.; Barletta, Justine A.; Guo, Junming; Swanson, Scott J.; Ruan, Daniel T.; Hanna, Glenn J.; Haddad, Robert I.; Getz, Gad; Kwiatkowski, David J.; Carter, Scott L.; Sabatini, David M.; Jänne, Pasi A.; Garraway, Levi A.; Lorch, Jochen H.

doi:10.1056/nejmoa1403352

Cited by 293 publications

(241 citation statements)

References 27 publications

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“…Similarly, Voss and colleagues found inactivating mutations in TSC1 or TSC2, or activating mutations in MTOR, in 4 of 6 renal cell carcinoma patients who had durable response to either everolimus or temsirolimus, but not in patients who progressed rapidly on the same treatments (37). Recently, TSC2 (Q1178X) loss-of-function mutation was identified in one thyroid cancer patient who achieved a complete response that lasted for 18 months when treated with everolimus (38). Despite lacking placebo arms for comparison in those studies, the remarkable clinical efficacy of mTORC1 inhibitors in distinct types of TSC1/TSC2-mutated tumors (bladder, kidney, thyroid, and liver cancer) suggests a strong correlation between TSC1/TSC2 loss-of-function and clinical efficacy of mTORC1 inhibitors such as everolimus.…”

Section: Discussionmentioning

confidence: 93%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 93%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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“…Stable disease for five months and disease progression were observed in one and three patients, respectively. Only one patient achieved a near-complete response that lasted for 18 months, followed by progressive disease [10].…”

Section: Novel Therapy For Pdct and Atcmentioning

confidence: 99%

“…Furthermore, the authors demonstrate that cells expressing MTOR F2108L remain sensitive to treatment with Torin1, a direct TOR kinase inhibitor, suggesting that patients harbouring mTOR mutation would be ideal candidates for clinical trials of selective mTOR kinase inhibitors [10].…”

Section: Resistance To Mtor Inhibitorsmentioning

confidence: 99%

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

F¹,

Tumino²,

Frasca³

2016

Endocrinol Metab Syndr

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Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare but highly aggressive malignancies with an extremely short survival. Poor prognosis is due to their unlimited growth, invasion, migration and resistance to common anticancer therapies. Advances in understanding the molecular alterations in thyroid carcinomas led to development of new therapeutic strategies such as kinase inhibitors. Although several of these compounds have been approved by FDA and EMA for the treatment of radioactive-iodine refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC), no significant clinical efficacy with targeted therapies have been observed in those patients.Herein, we review and summarize the preclinical in vitro evidences of mechanisms of resistance to kinase inhibitors currently used in PDTC and ATC patients.

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“…Everolimus, an mTOR inhibitor, has been a target for ATC patients carrying an mTOR mutation. One patient with ATC treated with everolimus had a reduction in tumor size in the first 18 months but progressed due to resistance to the treatment [18]. Microtubules are extremely important in the process of cell mitosis, and are therefore a potential target for anticancer therapy.…”

mentioning

confidence: 99%

Unravelling the best combination of therapies to treat anaplastic thyroid cancer

Abate

Smallridge

2016

Expert Review of Endocrinology & Metabolism

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Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Cited by 293 publications

References 27 publications

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

Unravelling the best combination of therapies to treat anaplastic thyroid cancer

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