Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation

Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma, commonly harboring a gain-of-function L122R mutation in the muscle-specific master transcription factor MYOD1. MYOD1-mutated ssRMS is almost invariably fatal, and development of novel therapeutic approaches based on the biology of the disease is urgently needed. MYOD1 L122R affects the DNA-binding domain and is believed to confer MYC-like properties to MYOD1, driving oncogenesis. Moreover, the majority of the MYOD1-mutated ssRMS harbor additional alterations activating the PI3K/AKT pathway. It is postulated that the PI3K/AKT pathway cooperates with MYOD1 L122R. To address this biological entity, we established and characterized a new patient-derived ssRMS cell line OHSU-SARC001, harboring MYOD1 L122R as well as alterations in PTEN, PIK3CA, and GNAS. We explored the functional impact of these aberrations on oncogenic signaling with gain-of-function experiments in C2C12 murine muscle lineage cells. These data reveal that PIK3CAI459_T462del, the novel PIK3CA variant discovered in this patient specimen, is a constitutively active kinase, albeit to a lesser extent than PI3KCAE545K, a hotspot oncogenic mutation. Furthermore, we examined the effectiveness of molecularly targeted PI3K/AKT/mTOR and RAS/MAPK inhibitors to block oncogenic signaling and suppress the growth of OHSU-SARC001 cells. Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options.

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Anaplastic Spindle Cell Squamous Carcinoma Arising from Tall Cell Variant Papillary Carcinoma of the Thyroid Gland: A Case Report and Review of the Literature

Case Reports in Endocrinology ◽

10.1155/2017/4581626 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Darren K. Patten ◽

Alia Ahmed ◽

Owain Greaves ◽

Roberto Dina ◽

Rashpal Flora ◽

...

Keyword(s):

Spindle Cell ◽

Treatment Options ◽

Squamous Carcinoma ◽

Newly Diagnosed ◽

Review Of The Literature ◽

Tall Cell Variant ◽

Aggressive Form ◽

Appropriate Treatment ◽

Tall Cell ◽

Cell Variant

Tall cell variant (TCV) of papillary thyroid carcinoma (PTC), an aggressive form of thyroid cancer, is characterised by 50% of cells with height that is three times greater than the width. Very rarely, some of these cancers can progress to spindle cell squamous carcinoma (SCSC) resulting in cancers with elements of both SCSC and TCV PTC. Here we report a case of SCSC arising from TCV PTC. In addition to this case, we have performed a literature review and compiled all published reports of SCSC arising from TCV PTC, including the nature of treatment and the prognosis for each of the 20 patients recorded. This is intended for use as a guide for clinicians in what the most appropriate treatment options may be for a newly diagnosed patient. Due to the rarity coupled with diagnosis occurring at a very advanced stage of disease progression, performing clinical trials is difficult and therefore drawing conclusions on optimal treatment methods remains a challenge.

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PIK3CA-Related Overgrowth Spectrum

Overgrowth Syndromes ◽

10.1093/med/9780190944896.003.0012 ◽

2019 ◽

pp. 217-240

Author(s):

Kim M. Keppler-Noreuil

Keyword(s):

Cell Growth ◽

Clinical Features ◽

Tissue Specificity ◽

Phenotypic Variability ◽

Akt Pathway ◽

Gain Of Function ◽

Clinical Phenotypes ◽

Segmental Overgrowth ◽

Postzygotic Mutations ◽

Cell Growth And Proliferation

Postzygotic mutations of the PIK3CA gene are associated with a series of clinical phenotypes characterized by segmental overgrowth and recently grouped under the term PIK3CA-related overgrowth spectrum (PROS). This chapter provides an overview of the clinical features shared by the phenotypes in PROS, including both the conditions with isolated features and the ones with syndromal presentation. The somatic overgrowth in cases with PROS is asymmetric, progressive, and “ballooning” in appearance and tends to involve predominantly the limbs, including fingers and toes, although the trunk and face are often affected as well. The tissues affected in the overgrowth can include all or some of these types: fibrous, adipose, vascular, nervous, and skeletal. Somatic gain-of-function mutations of PIK3CA cause activation of the PI3K-AKT pathway, leading to excessive cell growth and proliferation. Timing of PIK3CA mutations, tissue specificity, and type of mutation may play a role in the phenotypic variability of PROS.

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Classification of Mutations by Functional Impact Type: Gain of Function, Loss of Function, and Switch of Function

Bioinformatics Research and Applications - Lecture Notes in Computer Science ◽

10.1007/978-3-319-08171-7_21 ◽

2014 ◽

pp. 236-242

Author(s):

Mingming Liu ◽

Layne T. Watson ◽

Liqing Zhang

Keyword(s):

Loss Of Function ◽

Gain Of Function ◽

Functional Impact ◽

Function Loss

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Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway

Molecular Cancer ◽

10.1186/1476-4598-8-103 ◽

2009 ◽

Vol 8 (1) ◽

pp. 103 ◽

Cited By ~ 46

Author(s):

Peixin Dong ◽

Zhujie Xu ◽

Nan Jia ◽

Dajin Li ◽

Youji Feng

Keyword(s):

Endometrial Cancer ◽

Cancer Cells ◽

Akt Pathway ◽

Gain Of Function ◽

Elevated Expression

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Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Cancers ◽

10.3390/cancers12102795 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2795

Author(s):

Aadhya Tiwari ◽

Mari Iida ◽

Corinna Kosnopfel ◽

Mahyar Abbariki ◽

Apostolos Menegakis ◽

...

Keyword(s):

Cell Proliferation ◽

Triple Negative ◽

Mapk Pathway ◽

Binding Protein ◽

Akt Pathway ◽

Breast Cancers ◽

Gain Of Function ◽

Multifunctional Protein ◽

Cancer Hallmarks ◽

The Individual

The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.

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Targeted Therapies in Cancer: To Be or Not to Be, Selective

Biomedicines ◽

10.3390/biomedicines9111591 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1591

Author(s):

Skye Montoya ◽

Deborah Soong ◽

Nina Nguyen ◽

Maurizio Affer ◽

Sailasya P. Munamarty ◽

...

Keyword(s):

Targeted Therapies ◽

Drug Exposure ◽

Kinase Inhibitors ◽

De Novo ◽

Treatment Options ◽

Sequential Therapy ◽

Oncogenic Signaling ◽

Multikinase Inhibitor ◽

Cancer Types ◽

Goal Understanding

Development of targeted therapies in recent years revealed several nonchemotherapeutic options for patients. Chief among targeted therapies is small molecule kinase inhibitors targeting key oncogenic signaling proteins. Through competitive and noncompetitive inhibition of these kinases, and therefore the pathways they activate, cancers can be slowed or completely eradicated, leading to partial or complete remissions for many cancer types. Unfortunately, for many patients, resistance to targeted therapies, such as kinase inhibitors, ultimately develops and can necessitate multiple lines of treatment. Drug resistance can either be de novo or acquired after months or years of drug exposure. Since resistance can be due to several unique mechanisms, there is no one-size-fits-all solution to this problem. However, combinations that target complimentary pathways or potential escape mechanisms appear to be more effective than sequential therapy. Combinations of single kinase inhibitors or alternately multikinase inhibitor drugs could be used to achieve this goal. Understanding how to efficiently target cancer cells and overcome resistance to prior lines of therapy became imperative to the success of cancer treatment. Due to the complexity of cancer, effective treatment options in the future will likely require mixing and matching these approaches in different cancer types and different disease stages.

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Somatic IDH1 variant (p.R132C) in an adult male with Maffucci syndrome

Molecular Case Studies ◽

10.1101/mcs.a006127 ◽

2021 ◽

pp. mcs.a006127

Author(s):

Natasha J. Brown ◽

Zimeng Ye ◽

Chloe Stutterd ◽

Sureshni I. Jayasinghe ◽

Amy Schneider ◽

...

Keyword(s):

Adult Male ◽

Spindle Cell ◽

Malignant Tumors ◽

Digital Pcr ◽

Peripheral Blood Lymphocytes ◽

Pcr Analysis ◽

Gain Of Function ◽

Maffucci Syndrome ◽

Increased Risk ◽

Spindle Cell Hemangioma

Maffucci Syndrome is a rare, highly variable somatic mosaic condition and well-known cancer related gain-of-function variants in either the IDH1 or IDH2 genes have been found in the affected tissues of most reported patients. Features include benign enchondroma and spindle cell hemangioma, with a recognized increased risk of various malignancies. Fewer than 200 cases have been reported, therefore accurate estimates of malignancy risk are difficult to quantify and recommended surveillance guidelines are not available. The same gain-of-function IDH1 and IDH2 variants are also implicated in a variety of other benign and malignant tumors. An adult male presented with several soft palpable lesions on the right upper limb. Imaging and histopathology raised the possibility of Maffucci syndrome. DNA was extracted from peripheral blood lymphocytes and tissue surgically resected from a spindle-cell hemangioma. Sanger sequencing and Droplet-digital PCR analysis of the IDH1 gene was performed. We identified a somatic mosaic c.394C>T (p.R132C) variant in exon 5 of IDH1, in DNA derived from hemangioma tissue at ~ 17% mutant allele frequency. This variant was absent in DNA derived from blood. This variant has been identified in the affected tissue of most reported patients with Maffucci syndrome Although the patient has a potentially targetable variant, and there is a recognized risk of malignant transformation in this condition, a decision was made not to intervene with an IDH1 inhibitor. The reasons and prospects for therapy in this condition are discussed.

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Dermatofibrosarcoma protuberans – the use of neoadjuvant imatinib for treatment of an uncommon breast malignancy: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-019-2316-0 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 1

Author(s):

Matthew W. McGee ◽

Sarag A. Boukhar ◽

Varun Monga ◽

Ronald Weigel ◽

Sneha D. Phadke

Keyword(s):

Breast Carcinoma ◽

Tumor Size ◽

Spindle Cell ◽

Treatment Options ◽

Neoadjuvant Treatment ◽

Breast Conservation ◽

Dermatofibrosarcoma Protuberans ◽

Molecular Testing ◽

Correct Identification ◽

Metaplastic Breast Carcinoma

Abstract Background Dermatofibrosarcoma protuberans is a rare soft tissue malignancy that, if left untreated, can be locally destructive and life-threatening. Dermatofibrosarcoma protuberans is uncommon in the breast, and the similarity of its morphologic features with other spindle cell malignancies can make correct identification difficult. Immunohistochemistry and molecular testing can aid in the correct diagnosis when there is diagnostic uncertainty. Imatinib, a selective tyrosine kinase inhibitor, has been used for adjuvant treatment of dermatofibrosarcoma protuberans following surgical resection. When used as a neoadjuvant treatment, imatinib offers the opportunity to decrease tumor size prior to surgery to lessen the chance for disfigurement. Case presentation We present the case of a Caucasian woman who was 46-year-old when she first noted a mass in her right breast in 2015; she was initially diagnosed as having metaplastic breast carcinoma. Mastectomy and systemic chemotherapy were planned; however, after review of pathology at a referral center, the diagnosis was changed to dermatofibrosarcoma protuberans. She was treated with 4 months of neoadjuvant imatinib with adequate tumor shrinkage to perform breast conservation. Conclusion This patient’s case stresses the importance of correctly diagnosing this rare breast tumor through the histopathologic appearance of dermatofibrosarcoma protuberans, molecular pathogenesis, and immunohistochemistry. These techniques can help differentiate dermatofibrosarcoma protuberans from metaplastic breast carcinoma and other spindle cell lesions of the breast. This is critical, as the treatment options for metaplastic breast carcinoma significantly differ from treatment options for dermatofibrosarcoma protuberans. This case describes the use of imatinib as a neoadjuvant option to reduce preoperative tumor size and improve surgical outcomes.

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Unusual Glomus Tumor of the Penis

Current Urology ◽

10.1159/000442864 ◽

2015 ◽

Vol 9 (3) ◽

pp. 113-118 ◽

Cited By ~ 4

Author(s):

Gautam Dagur ◽

Kelly Warren ◽

Yimei Miao ◽

Navjot Singh ◽

Yiji Suh ◽

...

Keyword(s):

Clinical Presentation ◽

Spindle Cell ◽

Glomus Tumor ◽

Treatment Options ◽

Surgical Excision ◽

Primary Objective ◽

Inclusion Criteria ◽

Glomus Tumors ◽

Clinical Presentations ◽

Epithelial Lesions

Introduction: Glomus tumors are benign neoplasms commonly found in subungual regions of the extremities and rarely located in the penis. Misdiagnosis of glomus tumors is common; therefore, symptoms and clinical presentations should be reviewed. Objective: The primary objective of this review article is to emphasize the pathogenesis, pathology, clinical presentation, symptoms, diagnosis, and treatment methods of glomus tumors in order to better identify and manage the condition. Materials and Methods: Research was conducted using PubMed/Medline. The inclusion criteria required glomus tumor to be present on the penis. Results: Glomus tumors, which appear as symptomatic or asymptomatic lesions, are attributed to dispersion grouping of neoplastic or non-neoplastic lesions in a particular area. Conclusion: Differential diagnosis of glomus tumors includes hemangiomas, neurofibromatosis, epithelial lesions, and spindle-cell lesions. Physical examination and histological findings should be used for diagnosis. Treatment options can be either conservative or invasive, in which the patient undergoes surgical excision.

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