scholarly journals PI3K Promotes Basal Cell Carcinoma Growth Through Kinase-Induced p21 Degradation

2021 ◽  
Vol 11 ◽  
Author(s):  
Rachel Y. Chow ◽  
Ung Seop Jeon ◽  
Taylor M. Levee ◽  
Gurleen Kaur ◽  
Daniel P. Cedeno ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Kinase Inhibitor ◽  
Pi3k Pathway ◽  
Sequencing Analysis ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Pathway Expression ◽  
Hh Signaling

Basal cell carcinoma (BCC) is a locally invasive epithelial cancer that is primarily driven by the Hedgehog (HH) pathway. Advanced BCCs are a critical subset of BCCs that frequently acquire resistance to Smoothened (SMO) inhibitors and identifying pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify a PI3K pathway expression signature in BCC. Pharmacological inhibition of PI3K activity in BCC cells significantly reduces cell proliferation and HH signaling. However, treatment of Ptch1fl/fl; Gli1-CreERT2 mouse BCCs with the PI3K inhibitor BKM120 results in a reduction of tumor cell growth with no significant effect on HH signaling. Downstream PI3K components aPKC and Akt1 showed a reduction in active protein, whereas their substrate, cyclin-dependent kinase inhibitor p21, showed a concomitant increase in protein stability. Our results suggest that PI3K promotes BCC tumor growth by kinase-induced p21 degradation without altering HH signaling.

scholarly journals 483 Next-generation target sequencing analysis identifies multiple somatic mutations in basal cell carcinoma

2019 ◽  
Vol 139 (9) ◽  
pp. S297
Author(s):  
L. Di Nardo ◽  
C. Pellegrini ◽  
M. Maturo ◽  
F. Ricci ◽  
A. Di Stefani ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Somatic Mutations ◽  
Sequencing Analysis ◽  
Next Generation ◽  
Target Sequencing

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A ) gene in squamous cell carcinoma of the larynx

2004 ◽  
Vol 39 (3) ◽  
pp. 147-154 ◽  
Author(s):  
Robert Smigiel ◽  
Maria Sasiadek ◽  
Tomasz Krecicki ◽  
David Ramsey ◽  
Jozef Jagielski ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cdkn2a Gene ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Carcinoma Of The Larynx

scholarly journals Roles of the Hedgehog Signaling Pathway in Skin Development, Homeostasis and Cancer

2017 ◽  
Author(s):  
Yoshinori Abe ◽  
Nobuyuki Tanaka
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Basal Cell ◽  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Skin Development ◽  
Morphogenetic Protein ◽  
Hh Signaling

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

scholarly journals Novel alterations in IFT172 and KIFAP3 may induce basal cell carcinoma

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shoko Onodera ◽  
Nana Morita ◽  
Yuriko Nakamura ◽  
Shinichi Takahashi ◽  
Kazuhiko Hashimoto ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Somatic Mutations ◽  
Enrichment Analysis ◽  
Sequencing Analysis ◽  
Gorlin Syndrome ◽  
Driver Genes ◽  
Aged Patients ◽  
Basal Cell Carcinomas

Abstract Background Basal cell carcinoma (BCC) is the most commonly occurring neoplasm in patients with Gorlin syndrome. It is widely accepted that multiple basal cell carcinomas simultaneously develop in middle-aged patients with this syndrome. However, the presence of driver genes other than the PTCH1 in Gorlin syndrome has not been explored. This study aimed to identify common gene mutations other than PTCH1 in simultaneously occurring basal cell carcinomas in patients with Gorlin syndrome via exome sequencing analysis. Methods Next-generation sequencing analysis was performed using four basal cell carcinoma samples, one dental keratinocyte sample, and two epidermoid cyst samples, which were surgically resected from one patient with Gorlin syndrome on the same day. Results Overall, 282 somatic mutations were identified in the neoplasms. No additional somatic mutations in PTCH1, PTCH2, TP53, and SMO were identified. However, enrichment analysis showed that multiple genes, such as IFT172 and KIFAP3, could regulate ciliary functions important for Hedgehog signaling. Conclusion The development of BCCs in patients with Gorlin syndrome may be triggered by mutations that cause substantial dysfunction of cilia.

A phase I study of CX-4945 administered orally twice daily to patients with advanced basal cell carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS10080-TPS10080
Author(s):  
Zeynep Eroglu ◽  
Charles Lance Cowey ◽  
John Soong ◽  
Daniel McCormick ◽  
Phoebe Fan ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Target Genes ◽  
Objective Response ◽  
Locally Advanced ◽  
Eligibility Criteria ◽  
Hh Signaling ◽  
Advanced Basal Cell Carcinoma

TPS10080 Background: Smoothened inhibitors (SMOi) targeting the Hedgehog (Hh) pathway have been approved for the treatment of patients with locally advanced Basal Cell Carcinoma (laBCC) or metastatic BCC (mBCC). Unfortunately, resistance against SMO inhibitors (SMOi) can develop. Targeting the signaling cascade downstream of SMO, in this case via a novel small molecule inhibitor, could obviate this issue. Casein Kinase 2 (CK2) affects the terminal component of the Hh signaling pathway by promoting Gli2 stability and Gli2’s interaction with target genes. Given the interplay between CK2 and GLI-2 and the importance of Hh signaling activation, CX-4945, a potent CK2 inhibitor, may provide benefits for the BCC patients with resistance or intolerance to SMOi. Methods: A phase I trial (NCT03897036) to explore various treatment durations of CX-4945 was designed for patients with laBCC or mBCC; with endpoints include safety (CTCAE v5) and objective response rate by RECIST 1.0 for mBCC and composite response for laBCC. Major eligibility criteria include progression or intolerability to SMO inhibitors; laBCC patients must not be surgical candidates and must have received prior radiation unless contraindicated, and basosquamous histology is excluded. The first phase of the trial uses a 3+3 design to test the tolerance of a CX-4945 dose of 1000 mg bid for a duration of 28 days continuously. If 2 out of 3, or 2 out of 6 patients experience a DLT, the regimen of 1000 mg bid for 21 days followed by 7 days off (already tested in prior CX-4945 Phase I trials in other tumor types) will be selected as the recommend phase 2 dose (RP2D). Upon determining the RP2D, a dose-expansion phase will further evaluateCX-4945 in two cohorts (laBCC & mBCC), with 10 patients enrolled in each. Currently, we are enrolling patients and collecting sufficient data for the determination of RP2D in this patient population; thus, further assessments are required to determine the safety, tolerability, and efficacy of CX-4945 in advanced BCC. Clinical trial information: NCT03897036.

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