Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells ...from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors.
The molecular profiling of small-cell lung cancer is challenging because of the difficulty in obtaining suitable tumor samples for integrative genomic analysis. While an urgent need exists for ...well-defined and effective therapeutic targets in small-cell lung cancer, no significant improvement has been made in treating this disease over the past 30 years. Recently, three reports describing comprehensive genomic analyses of small-cell lung cancer have been published. These reports have provided a framework of biologically relevant genes in small-cell lung cancer and have demonstrated that the genomic landscape of small-cell lung cancer was almost equivalent between Asian and Caucasian populations. Of note, these three comprehensive genomic analyses and other molecular analyses of small-cell lung cancer have contributed to the identification of patient populations that may benefit from promising targeted agents, such as those affecting the PI3K/AKT/mTOR pathway, FGFR1, RET or AURORA kinase inhibitors. Targeting small-cell lung cancer cells with tumor suppressor gene alteration based on synthetic lethality is also promising. The present review provides an overview of the biologically relevant genetic alterations and targeted therapies of small-cell lung cancer focusing on recent discoveries that could impact the management of small-cell lung cancer.
KRAS mutations are predictive markers for the efficacy of anti-EGFR antibody therapies in patients with metastatic colorectal cancer. Although the mutational status of KRAS is reportedly highly ...concordant between primary and metastatic lesions, it is not yet clear whether genotoxic chemotherapies might induce additional mutations.
A total of 63 lesions (23 baseline primary, 18 metastatic and 24 post-treatment metastatic) from 21 patients who were treated with FOLFOX as adjuvant therapy for stage III/IV colorectal cancer following curative resection were examined. The DNA samples were obtained from formalin-fixed paraffin-embedded specimens, and KRAS, NRAS, BRAF and PIK3CA mutations were evaluated.
The numbers of primary lesions with wild-type and mutant KRAS codons 12 and 13 were 8 and 13, respectively. The mutational status of KRAS remained concordant between the primary tumours and the post-FOLFOX metastatic lesions, irrespective of patient background, treatment duration and disease-free survival. Furthermore, the mutational statuses of the other genes evaluated were also concordant between the primary and metastatic lesions.
Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumours and post-FOLFOX tumour metastases might serve as valid sources of DNA for known genomic biomarker testing.
Background: In the era of genome-guided personalized cancer treatment, it is important to understand genomic changes of tumors caused by chemotherapy. Here, we evaluated whether adjuvant FOLFOX ...chemotherapy modifies the mutational profile of recurrent colorectal cancers (CRC). Material and Methods: Whole exome sequencing was performed on primary CRC, untreated metastasis, and recurrent tumors following adjuvant FOLFOX chemotherapy resected from the same patients. We selected patients whose untreated metastasis and recurrent tumors occurred in the same organ to remove the influences by difference of metastatic site. The somatic mutation profiles were compared between patient-matched tumor samples. Results: Four CRC patients with appropriate tumor samples were analyzed. There was no significant differences in the number of mutations, the mutation spectrum, and the copy number changes in individual patients. The genomic signature resulting from L-OHP exposure (G>T/C>A, T>AIA>T transversions) was not increased after FOLFOX chemotherapy. Overlaps of the SNVs and indels remained 26-65% of each tumor samples between patient-matched tumor samples. One patient harbored AKT1 E17K mutation in the recurrent tumor, while PIK3CA E542K and E88Q mutations were detected in the primary and untreated metastasis. The genes related to intracellular Ca2+ homeostasis were enriched among post-FOLFOX unique mutated genes. Conclusion: Our data suggests adjuvant FOLFOX chemotherapy does not produce gene alterations in recurrent cotorectal tumors. The mutational discordance between patient-matched tumor samples are likely to be derived from tumor heterogeneity and clonal selection by the chemotherapy. These findings facilitate the elucidation of chemo-resistance and development of new treatment strategies.
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