KRAS as a Therapeutic Target McCormick, Frank
Clinical cancer research,
04/2015, Letnik:
21, Številka:
8
Journal Article
Recenzirano
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KRAS proteins play a major role in human cancer, but have not yielded to therapeutic attack. New technologies in drug discovery and insights into signaling pathways that KRAS controls have promoted ...renewed efforts to develop therapies through direct targeting of KRAS itself, new ways of blocking KRAS processing, or by identifying targets that KRAS cancers depend on for survival. Although drugs that block the well-established downstream pathways, RAF-MAPK and PI3K, are being tested in the clinic, new efforts are under way to exploit previously unrecognized vulnerabilities, such as altered metabolic networks, or novel pathways identified through synthetic lethal screens. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer further hope that new ways of treating KRAS are finally coming into view. These issues are discussed in this edition of CCR Focus.
The identification of mutationally activated BRAF in many cancers altered our conception of the part played by the RAF family of protein kinases in oncogenesis. In this Review, we describe the ...development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic. We discuss the spectrum of RAF mutations in human cancer and the complex interplay between the tissue of origin and the response to RAF inhibition. Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit not only the thousands of patients who are diagnosed annually with BRAF-mutated metastatic melanoma but also the larger patient population with malignancies harbouring mutationally activated RAF genes that are ineffectively treated with the current generation of BRAF kinase inhibitors.
Purpose To determine the prevalence of complications and reoperations during and after hip arthroscopy. Methods A systematic review of multiple medical databases was performed using the Preferred ...Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist. All clinical outcome studies that reported the presence or absence of complications and/or reoperations were eligible for inclusion. Length of follow-up was not an exclusion criterion. Complication and reoperation rates were extracted from each study. Duplicate patient populations within separate distinct publications were analyzed and reported only once. Results Ninety-two studies (6,134 participants) were included. Most were Level IV evidence studies (88%) with short-term follow-up (mean 2.0 years). Labral tears and femoroacetabular impingement (FAI) were the 2 most common diagnoses treated, and labral treatment and acetabuloplasty/femoral osteochondroplasty were the 2 most common surgical techniques reported. Overall, major and minor complication rates were 0.58% and 7.5%, respectively. Iatrogenic chondrolabral injury and temporary neuropraxia were the 2 most common minor complications. The overall reoperation rate was 6.3%, occurring at a mean of 16 months. Total hip arthroplasty (THA) was the most common reoperation. The conversion rate to THA was 2.9%. Conclusions The rate of major complications was 0.58% after hip arthroscopy. The reoperation rate was 6.3%, and the most common reason for reoperation was conversion to THA. Minor complications and the reoperation rate are directly related to the learning curve of hip arthroscopy. As surgical indications evolve, patient selection should limit the number of cases that would have been converted to THA. Similarly, the number of minor complications is directly related to technical aspects of the procedure and therefore will decrease with surgeon experience and improvement in instrumentation. Level of Evidence Level IV, a systematic review of Level I to IV studies.
Our understanding of how the RAS protein family, and in particular mutant KRAS promote metabolic dysregulation in cancer cells has advanced significantly over the last decade. In this Review, we ...discuss the metabolic reprogramming mediated by oncogenic RAS in cancer, and elucidating the underlying mechanisms could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers.
Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were ...discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.
Purpose The purpose of this study was to quantify the current trends in knee cartilage surgical techniques performed in the United States from 2004 through 2011 using a large private-payer database. ...A secondary objective was to identify salient demographic factors associated with these procedures. Methods We performed a retrospective database review using a large private-payer medical record database within the PearlDiver database. The PearlDiver database is a publicly available, Health Insurance Portability and Accountability Act–compliant national database compiled from a collection of private insurer records. A search was performed for surgical techniques in cartilage palliation (chondroplasty), repair (microfracture/drilling), and restoration (arthroscopic osteochondral autograft, arthroscopic osteochondral allograft, autologous chondrocyte implantation, open osteochondral allograft, and open osteochondral autograft). The incidence, growth, and demographic factors associated with the surgical procedures were assessed. Results From 2004 through 2011, 198,876,000 patients were analyzed. A surgical procedure addressing a cartilage defect was performed in 1,959,007 patients, for a mean annual incidence of 90 surgeries per 10,000 patients. Across all cartilage procedures, there was a 5.0% annual incidence growth (palliative, 3.7%; repair, 0%; and restorative, 3.1%) ( P = .027). Palliative techniques (chondroplasty) were more common (>2:1 ratio for repair marrow-stimulation techniques and 50:1 ratio for restoration autologous chondrocyte implantation and osteochondral autograft and allograft). Palliative surgical approaches were the most common technique, regardless of age, sex, or region. Conclusions Articular cartilage surgical procedures in the knee are common in the United States, with an annual incidence growth of 5%. Surgical techniques aimed at palliation are more common than cartilage repair and restoration techniques regardless of age, sex, or region. Level of Evidence Level IV, retrospective database analysis.
Purpose The purposes of this study were (1) to analyze long-term outcomes in patients who have undergone open or arthroscopic Bankart repair and (2) to evaluate study methodologic quality through ...validated tools. Methods We performed a systematic review of Level I to IV Evidence using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical outcome studies after open or arthroscopic Bankart repair with a minimum of 5 years' follow-up were analyzed. Clinical and radiographic outcomes were extracted and reported. Study methodologic quality was evaluated with Modified Coleman Methodology Scores and Quality Appraisal Tool scores. Results We analyzed 26 studies (1,781 patients). All but 2 studies were Level III or IV Evidence with low Modified Coleman Methodology Scores and Quality Appraisal Tool scores. Patients analyzed were young (mean age, 28 years) male patients (81%) with unilateral dominant shoulder (61%), post-traumatic recurrent (mean of 11 dislocations before surgery) anterior shoulder instability without significant glenoid bone loss. The mean length of clinical follow-up was 11 years. There was no significant difference in recurrence of instability with arthroscopic (11%) versus open (8%) techniques ( P = .06). There was no significant difference in instability recurrence with arthroscopic suture anchor versus open Bankart repair (8.5% v 8%, P = .82). There was a significant difference in rate of return to sport between open (89%) and arthroscopic (74%) techniques ( P < .01), whereas no significant difference was observed between arthroscopic suture anchor (87%) and open repair (89%) ( P = .43). There was no significant difference in the rate of postoperative osteoarthritis between arthroscopic suture anchor and open Bankart repair (26% and 33%, respectively; P = .059). There was no significant difference in Rowe or Constant scores between groups ( P > .05). Conclusions Surgical treatment of anterior shoulder instability using arthroscopic suture anchor and open Bankart techniques yields similar long-term clinical outcomes, with no significant difference in the rate of recurrent instability, clinical outcome scores, or rate of return to sport. No significant difference was shown in the incidence of postoperative osteoarthritis with open versus arthroscopic suture anchor repair. Study methodologic quality was poor, with most studies having Level III or IV Evidence. Level of Evidence Level IV, systematic review of studies with Level I through IV Evidence.
H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual ...tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, whereas wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTK). We show that both are necessary for exponential growth of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to the hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death.
The results of this study highlight a novel role for wild-type Ras signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these findings reveal that therapeutically targeting oncogenic Ras signaling alone may be ineffective owing to feedback activation of RTKs, and suggest that blocking upstream RTKs in combination with downstream effector pathways may be beneficial in the treatment of Ras-mutant tumors.
Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the ...survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.
Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate ...of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.
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