https://repub.eur.nl/pub/129868/Repub_129868.pdf

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.

The DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase composed of a large catalytic subunit (DNA-PKcs) and the Ku70/80 heterodimer. Over the past two decades, significant progress has been made in elucidating the role of DNA-PK in non-homologous end joining (NHEJ), the major pathway for repair of ionizing radiation-induced DNA double strand breaks in human cells and recently, additional roles for DNA-PK have been reported. In this review, we will describe the biochemistry, structure and function of DNA-PK, its roles in DNA double strand break repair and its newly described roles in mitosis and other cellular processes.

The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis

The DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery that governs the response to DNA damage, serving to maintain genome integrity. However, the DNA-PK kinase component was initially isolated with transcriptional complexes, and recent findings have illuminated the impact of DNA-PK–mediated transcriptional regulation on tumor progression and therapeutic response. DNA-PK expression has also been correlated with poor outcome in selected tumor types, further underscoring the importance of understanding its role in disease. Herein, the molecular and cellular consequences of DNA-PK are considered, with an eye toward discerning the rationale for therapeutic targeting of DNA-PK.

Significance: Although DNA-PK is classically considered a component of damage response, recent findings illuminate damage-independent functions of DNA-PK that affect multiple tumor-associated pathways and provide a rationale for the development of novel therapeutic strategies. Cancer Discov; 4(10); 1126–39. ©2014 AACR .

https://cancerdiscovery.aacrjournals.org/content/candisc/4/10/1126.full.pdf

Beyond DNA Repair: DNA-PK Function in Cancer

5′ strand resection at DNA double strand breaks (DSBs) is critical for homologous recombination (HR) and genomic stability. Here we develop a novel method to quantitatively measure single-stranded DNA intermediates in human cells and find that the 5′ strand at endonuclease-generated break sites is resected up to 3.5 kb in a cell cycle–dependent manner. Depletion of CtIP, Mre11, Exo1 or SOSS1 blocks resection, while depletion of 53BP1, Ku or DNA-dependent protein kinase catalytic subunit leads to increased resection as measured by this method. While 53BP1 negatively regulates DNA end processing, depletion of Brca1 does not, suggesting that the role of Brca1 in HR is primarily to promote Rad51 filament formation, not to regulate end resection.

/pdf/quantitation-of-dna-double-strand-break-resection-5b181ta22f.pdf

Quantitation of DNA double-strand break resection intermediates in human cells

DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.

/pdf/dna-damage-checkpoint-kinases-in-cancer-ipwkxeyc6s.pdf

DNA damage checkpoint kinases in cancer

ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib

// Wani Arjumand 1, 2, 4 , Cole D. Merry 1, 2 , Chen Wang 1, 2 , Elias Saba 1, 2 , John B. McIntyre 3 , Shujuan Fang 1, 2 , Elizabeth Kornaga 3 , Prafull Ghatage 4 , Corinne M. Doll 2, 4 , Susan P. Lees-Miller 1, 2, 4 1 Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada 2 Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada 3 Translational Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada 4 Department of Oncology, University of Calgary, Calgary, Alberta, Canada Correspondence to: Susan P. Lees-Miller, email: leesmill@ucalgary.ca Corinne Doll, email: Corinne.Doll@albertahealthservices.ca Keywords: PI3K pathway, PIK3CA-E545K, Akt, GDC-0941, cisplatin Received: February 11, 2016     Accepted: July 18, 2016     Published: July 30, 2016 ABSTRACT The phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signaling pathway is activated in many human cancers. Previously, we reported that patients with early stage cervical cancer whose tumours harbour PIK3CA exon 9 or 20 mutations have worse overall survival in response to treatment with radiation and cisplatin than patients with wild-type PIK3CA . The purpose of this study was to determine whether PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin and/or radiation, and whether PI3K inhibition reverses the phenotype. We found that CaSki cells that are heterozygous for the PIK3CA -E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA . Similarly, HeLa cells engineered to stably express PIK3CA -E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA -E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. Our results suggests that cervical cancer patients whose tumours are positive for the PIK3CA -E545K mutation may benefit from PI3K inhibitor therapy in concert with standard cisplatin and radiation therapy.

/pdf/phosphatidyl-inositol-3-kinase-pik3ca-e545k-mutation-confers-4nhqa3u7lw.pdf

Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells.

DNA damage can occur as a result of endogenous metabolic reactions and replication stress or from exogenous sources such as radiation therapy and chemotherapy. DNA double strand breaks are the most cytotoxic form of DNA damage, and defects in their repair can result in genome instability, a hallmark of cancer. The major pathway for the repair of ionizing radiation-induced DSBs in human cells is nonhomologous end joining. Here we review recent advances on the mechanism of nonhomologous end joining, as well as new findings on its component proteins and regulation.

/pdf/detection-and-repair-of-ionizing-radiation-induced-dna-mfkym23tn4.pdf

Detection and Repair of Ionizing Radiation-Induced DNA Double Strand Breaks: New Developments in Nonhomologous End Joining

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ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib

Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells.

Detection and Repair of Ionizing Radiation-Induced DNA Double Strand Breaks: New Developments in Nonhomologous End Joining