75 Loss of PTEN leads to acquired resistance to the PI3Ka inhibitor BYL719: a case of convergent evolution under selective therapeutic pressure

Castel, Pau; Juric, Dejan; Griffith, Malachi; Griffith, Obi L.; Won, Helen; Ainscough, Benjamin; Ellis, Haley; Ebbesen, Saya H.; Gopakumar, Iyer; Quadt, Cornelia; Peters, Malte; Solit, David B.; Lowe, S. W.; Mardis, Elaine R.; Berger, Michael F.; Scaltriti, M.; Baselga, J.

doi:10.1016/s0959-8049(14)70201-1

Cited by 2 publications

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“…The role of PTEN loss as a resistance mechanism to the PI3K-alpha inhibitor, BYL719, which is currently in clinical trials for HNSCC, was recently reported in breast cancer. Juric et al 11,45 demonstrated that loss PTEN expression was identified in progressing lesions of a patient with PIK3CA-mutated metastatic breast cancer who initially responded to BYL719, however, the disease progressed rapidly, followed by death. Our data, indicating almost 24% of PIK3CA-mutated patients also exhibit loss of PTEN expression, together with these clinical findings, suggest the importance of a multiplatform approach of molecular profiling, which includes assessment of PTEN protein levels by IHC.…”

Section: Discussionmentioning

confidence: 99%

“…9 PIK3CA inhibitors, therefore, are a promising drug class that may provide treatment success, however, these agents have failed as monotherapy, in other tumor types, and resistance mechanisms have emerged. 10,11 Immunomodulatory agents also share promise as a therapeutic strategy for HNSCC due to the role of adaptive immune resistance to allow for tumor development in HPVassociated HNSCC. 12 Tumor molecular profile-guided treatment has been successfully utilized to identify molecular targets in patients with metastatic solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Molecular profiling of head and neck squamous cell carcinoma

et al. 2015

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BackgroundHead and neck squamous cell carcinoma (HNSCC) exhibits high rates of recurrence, and with few approved targeted agents, novel treatments are needed. We analyzed a molecular profiling database for the distribution of biomarkers predictive of chemotherapies and targeted agents.MethodsSeven hundred thirty‐five patients with advanced HNSCC (88 with known human papillomavirus [HPV] status), were profiled using multiple platforms (gene sequencing, gene copy number, and protein expression).ResultsAmong the entire patient population studied, epidermal growth factor receptor (EGFR) was the protein most often overexpressed (90%), TP53 gene most often mutated (41%), and phosphatidylinositol 3‐kinase (PIK3CA) most often amplified (40%; n = 5). With the exception of TP53 mutation, other biomarker frequencies were not significantly different among HPV‐positive or HPV‐negative patients. PIK3CA mutations and phosphatase and tensin homolog (PTEN) loss are frequent events, independent of HPV status. The immune response‐modulating programmed cell death 1 (PD1) and programmed cell death ligand 1 (PDL1) axis was active across sites, stages, and HPV status.ConclusionMolecular profiling utilizing multiple platforms provides a range of therapy options beyond standard of care. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1625–E1638, 2016

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular profiling of head and neck squamous cell carcinoma

et al. 2015

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“…In another study with findings potentially relevant to lymphoma, MYC and eIF4E network upregulation was found to mediate resistance to the combined PI3K/mTOR inhibitor Bez235 (Ilic et al , ). In colorectal and lung cancer, loss of expression of PTEN protein has been shown to be involved in resistance to PI3K inhibitors (Castel et al , ; Garza et al , ), although it remains to be seen whether this mechanism of resistance is limited to drugs which target p110‐α. Finally, acquired amplification of PIK3CA has been demonstrated as a novel mechanism of resistance in a breast cancer cell line treated with pictilisib (GDC‐0941), a drug with both alpha‐ and delta‐isoform selectivity that is currently under investigation in lymphoma (Huw et al , ).…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting PI3‐kinase (PI3K), AKT and mTOR axis in lymphoma

Blachly

Baiocchi

2014

Br J Haematol

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Targeted therapy represents a transformation in oncology, a field that has relied primarily on non-selective cytotoxic therapies. Phosphatidylinositol 3-kinase (PI3K) is a family of ubiquitous signalling molecules involved in a wide variety of cellular processes and likewise, in a broad selection of human cancers. The discovery that the p110-δ form of PI3K is differentially expressed in normal and malignant lymphocytes has led to the development of specific inhibitors that are currently in clinical trials for lymphoma. Downstream effectors of PI3K, including v-akt murine thymoma viral oncogene homolog 1 (AKT; also termed AKT1) and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) are similarly important in lymphoma, and agents targeting these components of the PI3K-AKT-mTOR axis are also underway, although at earlier stages of development. In this review we examine the role of PI3K-AKT-mTOR in normal and malignant lymphocytes, as well as the preclinical and clinical status of a number of inhibitors of this pathway.

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75 Loss of PTEN leads to acquired resistance to the PI3Ka inhibitor BYL719: a case of convergent evolution under selective therapeutic pressure

Cited by 2 publications

References 0 publications

Molecular profiling of head and neck squamous cell carcinoma

Molecular profiling of head and neck squamous cell carcinoma

Targeting PI3‐kinase (PI3K), AKT and mTOR axis in lymphoma

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