PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer

Wang, Qiang; Shi, Yanlong; Zhou, Kai; Wang, Lili; Yan, Zexuan; Liu, Yulin; Xu, Lili; Zhao, Shiwei; Chu, Huili; Shi, Tingting; Ma, Qiang; Bi, Jian

doi:10.1038/s41419-018-0776-6

Cited by 104 publications

(88 citation statements)

References 53 publications

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“…Furthermore, SK-OV-3/DDP cells are artificial cells induced by SK-OV-3. Various resistance studies have been performed with native cells ( 18 , 30 , 31 ). Therefore, native cells were chosen to explore the roles and mechanisms of the Hh pathway in the effectiveness of DDP in ovarian cancer.…”

Section: Resultsmentioning

confidence: 99%

The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer

Zhang

Cheng

et al. 2020

Oncol Rep

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Various studies have revealed that the Hedgehog (Hh) signaling pathway promotes ovarian cancer invasion, migration and drug resistance. Previous studies by our group have identified a set of genes, including multidrug resistance gene 1 (MDR1), that are regulated by Hh signaling in ovarian cancer. However, the association between Hh signaling activation and MDR1 expression requires further validation. In the present study, reverse transcription-quantitative PCR or western blot assays were used to evaluate the mRNA and protein expression levels of MDR1, Sonic Hh (Shh), glioma-associated oncogene 2 (Gli2), Gli1 and γ-phosphorylated H2A.X variant histone (γ-H2AX). MTT and colony-formation assays were performed to determine the effect of cisplatin (DDP) after inhibiting the Hh pathway in ovarian cancer cells. The results indicated that MDR1, Gli2 and Shh levels were much higher in SK-OV-3 cells with acquired DDP resistance than in native SK-OV-3 cells. ES-2 cells with overexpression of Gli2 were capable of efficiently forming colonies in the presence of low DDP concentrations. By contrast, Gli2 knockdown in SK-OV-3 cells decreased the colony-forming ability under the same concentration of DDP. As determined by MTT assays, knockdown of Gli2 or targeting of the Hh signaling pathway with either Gli-antagonist 61 (GANT61) or cyclopamine, in combination with DDP treatment, diminished the viability of ES-2 and SK-OV-3 cells, whereas Gli2 overexpression increased the viability of ES-2 cells in the presence of DDP. Knockdown of Gli2 or targeting the Hh signaling pathway with GANT61 also increased γ-H2AX levels but decreased the expression of MDR1 in the presence of DDP. MDR1 expression is regulated by the Hh signaling pathway and is likely a downstream transcription factor of Gli2. In conclusion, targeting the Hh signaling pathway increases the sensitivity of ovarian cancer to DDP. MDR1 is a target gene of the Hh signaling pathway and this pathway may affect chemoresistance of ovarian cancer to DDP via MDR1.

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Section: Resultsmentioning

confidence: 99%

The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer

Zhang

Cheng

et al. 2020

Oncol Rep

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“…Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate phosphoinositidies at the D3 position of the inositol and produce intracellular messengers regulating proliferation, adhesion, and migration. Mutations in the p110alpha subunit ( PIK3CA ) are associated with anti-cancer drug resistance, aggressive histologic features, and poor overall survival [ 26 , 27 ]. Similar effects, as already described above, (forward mutations) were observed for KRAS (PAT4), NRAS and SMAD4 (PAT5) and BRAF (PAT6).…”

Section: Discussionmentioning

confidence: 99%

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Ottaiano

Caraglia

Mauro

et al. 2020

Cancers

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Genetic dynamics underlying cancer progression are largely unknown and several genes involved in highly prevalent illnesses (e.g., hypertension, obesity, and diabetes) strongly concur to cancer phenotype heterogeneity. To study genotype-phenotype relationships contributing to the mutational evolution of colorectal cancer (CRC) with a focus on liver metastases, we performed genome profiling on tumor tissues of CRC patients with liver metastatic disease and no co-morbidities. We studied 523 cancer-related genes and tumor-immune microenvironment characteristics in primary and matched metastatic tissues. We observed a loss of KRAS and SMAD4 alterations and a high granzyme-B+ T-cell infiltration when the disease did not progress. Conversely, gain in KRAS, PIK3CA and SMAD4 alterations and scarce granzyme-B+ T-cells infiltration were observed when the tumor evolved towards a poly-metastatic spread. These findings provide novel insights into the identification of tumor oligo-metastatic status, indicating that some genes are on a boundary line between these two clinical settings (oligo- vs. poly-metastatic CRC). We speculate that the identification of these genes and modification of their evolution could be a new approach for anti-cancer therapeutic strategies.

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“…A recent meta-analysis covering twenty-eight studies enrolling 12,747 patients did not demonstrate a substantial prognostic role of PIK3CA mutation status in CRC [109]. However, several reports suggest that PI3KCA mutations, especially in exon 20, are linked to clinical resistance of anti-EGFR therapies [40,110] and to first-line chemotherapy [111]. It is difficult to evaluate the importance of PIK3CA as an independent predictive marker [40] as PIKC3A mutations often co-occur with RAS or BRAF mutations.…”

Section: Pi3kcamentioning

confidence: 99%

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

Koncina

Haan

Rauh

et al. 2020

Cancers

176

151

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Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in RAS, along with the mismatch repair gene deficiency, are currently routinely tested in clinics. Such biomarkers provide information for patient risk stratification and for the choice of the best treatment options. Nevertheless, reliable and powerful prognostic markers that can identify “high-risk” CRC patients, who might benefit from adjuvant chemotherapy, in early stages, are currently missing. To bridge this gap, genomic information has increasingly gained interest as a potential method for determining the risk of recurrence. However, due to several limitations of gene-based signatures, these have not yet been clinically implemented. In this review, we describe the different molecular markers in clinical use for CRC, highlight new markers that might become indispensable over the next years, discuss recently developed gene expression-based tests and highlight the challenges in biomarker research.

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PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer

Cited by 104 publications

References 53 publications

The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer

The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

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