K-ras Mutations In Pancreatic Cancer Research Articles

Emerging role of the KRAS-PDK1 axis in pancreatic cancer.

Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and it has the grim supremacy in terms of unfavourable survival rates. There have been great advances in survival rates for many types of cancers over the past few decades but hardly any change for pancreatic cancer. Mutations of the Ras oncogene are the most frequent oncogenic alterations in human cancers. The frequency of KRAS mutations in pancreatic cancer is around 90%. Given the well-established role of KRAS in cancer it is not surprising that it is one of the most attractive targets for cancer therapy. Nevertheless, during the last thirty years all attempts to target directly KRAS protein have failed. Therefore, it is crucial to identify downstream KRAS effectors in order to develop specific drugs able to counteract activation of this pathway. Among the different signalling pathways activated by oncogenic KRAS, the phosphoinositide 3-Kinase (PI3K) pathway is emerging as one of the most critical KRAS effector. In turn, PI3K activates several parallel pathways making the identification of the precise effectors activated by KRAS/PI3K more difficult. Recent data identify 3-phosphoinositide-dependent protein kinase 1 as a key tumour-initiating event downstream KRAS interaction with PI3K in pancreatic cancer.

317. Multiplex Bi-Functional Short-Hairpin RNA (shRNA) Targeting Single-Nucleotide KRAS Mutations in Pancreatic Cancer

317. Multiplex Bi-Functional Short-Hairpin RNA (shRNA) Targeting Single-Nucleotide KRAS Mutations in Pancreatic Cancer

Epidermal growth factor receptor-targeted treatment strategies in advanced pancreatic cancer: Is K-RAS mutational testing ready for prime time?

The combination of gemcitabine with erlotinib is viewed as one standard in the treatment of patients with advanced pancreatic cancer. However, the magnitude of the survival benefit of the combination therapy compared to single agent gemcitabine is relatively small. Whether this statistically significant survival benefit translates to a relevant clinical benefit of the combined treatment in view of increased toxicity and costs is still a matter of debate. Consequently, there has been great interest in identifying molecular biomarkers predictive for response and survival benefit from EGFR-targeted agents in advanced pancreatic cancer. No data have been published up to now concerning the value of K-RAS mutations in pancreatic cancer as a predictive marker for lack of response to EGFR targeted agents. Nevertheless, the first prospective evaluation of K-RAS status and response to erlotinib in combination with either gemcitabine or capecitabine suggest a significant improvement of overall survival only for patients with K-RAS wild type tumors suggesting a possible role of K-RAS mutational status as predictive marker in pancreatic cancer.

Impact of KRAS Mutations on Clinical Outcomes in Pancreatic Cancer Patients Treated with First-line Gemcitabine-Based Chemotherapy

Although erlotinib has become an important therapeutic option in addition to gemcitabine, the high frequency of KRAS mutations in pancreatic cancer probably limits the benefits. We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine-based chemotherapy. KRAS mutations were analyzed by sequencing codons 12, 13, and 61. In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 (n = 70) and 61 (n = 1) of KRAS. KRAS mutation was not associated with clinicopathologic parameters. Patients with KRAS mutations showed a worse response (11.3%) than those with wild-type KRAS (26.2%) and poor survival (mutant KRAS, 5.8 months vs. wild-type KRAS, 8.0 months; P = 0.001). Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (P < 0.001; HR = 0.437, 95% CI: 0.301-0.634), locally advanced disease (P < 0.001; HR = 0.417, 95% CI: 0.255-0.681), response to first-line chemotherapy (P = 0.003; HR = 0.482, 95% CI: 0.297-0.780), and wild-type KRAS (P = 0.001; HR = 0.523, 95% CI: 0.355-0.770). However, the observed survival advantage is derived from the subgroup of patients treated with gemcitabine/erlotinib (9.7 vs. 5.2 months; P = 0.002), whereas no survival difference based on KRAS mutation status is obvious in the other subgroup of patients treated without erlotinib (7.0 vs. 7.0 months; P = 0.121). These results need to be further explored in upcoming prospective studies to provide a rationale for personalized medicine in pancreatic cancer.

Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer

Organochlorine compounds such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE), and some polychlorinated biphenyls (PCBs) are carcinogenic to animals and possibly also to human beings. Occupational exposure to DDT may increase the risk of pancreas cancer. The high frequency of K-ras mutations in pancreatic cancer remains unexplained. We analysed the relation between serum concentrations of selected organochlorine compounds and mutations in codon 12 of the K-ras gene in patients with exocrine pancreatic cancer. Cases were prospectively identified in five hospitals. Mutations in K-ras were analysed by PCR and artificial restriction fragment length polymorphism. Cases of pancreatic cancer with wild-type K-ras (n=17) were frequency matched for age and sex to cases of pancreatic cancer with a K-ras mutation (n=34, case-case study). These 51 cases were further compared with 26 hospital controls (case-control comparison). Serum organochlorine concentrations were measured by high-resolution gas chromatography with electron-capture detection and negative ion chemical ionisation mass spectrometry. Serum concentrations of p,p'-DDT were significantly higher in pancreatic cancer cases with a K-ras mutation than in cases without a mutation (odds ratio for upper tertile 8.7 [95% CI 1.6-48.5], p for trend=0.005). For p,p'-DDE the corresponding figures were 5.3 (1.1-25.2, p for trend=0.031). These estimates held after adjusting for total lipids, other covariates, and total PCBs. A specific association was observed between a glycine to valine substitution at codon 12 and both p,p'-DDT and p,p'-DDE concentrations (odds ratio 15.9, p=0.044 and odds ratio 24.1, p=0.028; respectively). A similar pattern was shown for the major di-ortho-chlorinated PCBs (congeners 138, 153, and 180), even after adjustment for p,p'-DDE, but without a specific association with spectrum. Concentrations of p,p'-DDT and p,p'-DDE were similar among wild-type cases and controls, but significantly higher for K-ras mutated cases than for controls (p<0.01). Organochlorine compounds such as p,p'-DDT, p,p'-DDE, and some PCBs could play a part in the pathogenesis of exocrine pancreatic cancer through modulation of K-ras activation. The results require replication, but they suggest new roles for organochlorines in the development of several cancers in human beings.