bims-pimaco 2021-04-25 papers

Nat Commun. 2021 Apr 20. 12(1): 2335

RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways.

Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.

DOI: https://doi.org/10.1038/s41467-021-22531-3

World J Clin Cases. 2021 Apr 16. 9(11): 2458-2468

Relationship between mismatch repair protein, RAS, BRAF, PIK3CA gene expression and clinicopathological characteristics in elderly colorectal cancer patients.

Jun-Zhen Fan, Gao-Fei Wang, Xue-Bin Cheng, Zhou-Huan Dong, Xin Chen, Yu-Jiao Deng, Xin Song.

BACKGROUND: Colorectal cancer (CRC) is common in elderly patients. Mismatch repair (MMR) protein deletion is one of the causes of CRC. The RAS (KRAS/NRAS), BRAF, and PIK3CA genes are important gene targets in CRC treatment and are closely related to the prognosis and survival of patients. However, little is known regarding the relationship between the expression of MMR, RAS, BRAF, PIK3CA and the clinicopathological features in CRC patients.
AIM: To analyze the relationship between the expression of MMR, RAS, BRAF, PIK3CA and the clinicopathological features in CRC.
METHODS: A total of 327 elderly patients with CRC were enrolled, and immuno-histochemistry was used to detect the MMR protein. Real-time quantitative polymerase chain reaction was used to detect the RAS (KRAS/NRAS), BRAF, and PIK3CA genes. The clinicopathological data of the patients were recorded and analyzed by SPSS 19.0 statistical software.
RESULTS: In 327 elderly patients with CRC, the rate of MMR protein loss was 9.79% (32/327), and the deletion rate of four MMR proteins (MSH2, MSH6, MLH1, PMS2) was 1.83% (6/327), 3.06% (10/327), 7.65% (25/327), and 7.65% (25/327), respectively. There were no significant differences between MMR protein deletion and sex, pathological type, tumor morphology, differentiation degree or lymph node metastasis (P > 0.05), but there was a significant difference between MMR protein deletion and tumor diameter and tumor location (P = 0.048/P = 0.000). The mutation rates of the KRAS, NRAS, BRAF and PIK3CA genes in elderly CRC patients were 44.95% (147/327), 2.45% (8/327), 3.36% (11/327) and 2.75% (9/327), respectively; the KRAS gene mutation was closely related to tumor morphology (P = 0.002) but not to other clinicopathological features (P > 0.05), and there were no significant differences between NRAS gene mutation and clinicopathological features (P > 0.05). The BRAF gene mutation showed a significant difference in pathological type, tumor location, differentiation degree and lymph node metastasis (P < 0.05), but was not correlated with sex, tumor size and tumor morphology (P > 0.05). The PIK3CA gene mutation showed no significant differences in the above clinicopathological characteristics (P > 0.05). Significant differences were observed between MMR protein deletion and KRAS, BRAF, and PIK3CA gene mutations in elderly CRC patients (P = 0.044, P = 0.000, P = 0.003, respectively), but there was no significant difference between MMR protein deletion and NRAS mutation (P > 0.05).
CONCLUSION: In elderly CRC patients, the tumor is mainly located in the right colon, and the deletion rate of MMR protein is higher when the tumor diameter is greater than or equal to 5 cm; the deletion rate of MLH1 and PMS2 is more common; the mutation rate of KRAS gene is higher than that of the NRAS, BRAF and PIK3CA genes, the BRAF gene mutation has different degrees of correlation with clinicopathological characteristics; when the MMR protein is deleted, the BRAF and PIK3CA gene mutations are often present, and the KRAS gene mutation rate is low.

Keywords: Colorectal cancer; Diagnosis; Elderly patients; Expression; Gene mutation; Mismatch repair protein

DOI: https://doi.org/10.12998/wjcc.v9.i11.2458

Crit Rev Oncol Hematol. 2021 Apr 15. pii: S1040-8428(21)00122-0. [Epub ahead of print] 103334

PI3K INHIBITION IN BREAST CANCER: IDENTIFYING AND OVERCOMING DIFFERENT FLAVORS OF RESISTANCE.

Silvia Rita Vitale, Federica Martorana, Stefania Stella, Gianmarco Motta, Nicola Inzerilli, Michele Massimino, Elena Tirrò, Livia Manzella, Paolo Vigneri.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.

Keywords: Breast cancer; PI3K; PI3K-inhibitors; PI3K/AKT/mToR pathway; PIK3CA Mutations

DOI: https://doi.org/10.1016/j.critrevonc.2021.103334

Cell Cycle. 2021 Apr 20. 1-17

The emerging relationship between metabolism and DNA repair.

Danilo Cucchi, Amy Gibson, Sarah A Martin.

The DNA damage response (DDR) consists of multiple specialized pathways that recognize different insults sustained by DNA and repairs them where possible to avoid the accumulation of mutations. While loss of activity of genes in the DDR has been extensively associated with cancer predisposition and progression, in recent years it has become evident that there is a relationship between the DDR and cellular metabolism. The activity of the metabolic pathways can influence the DDR by regulating the availability of substrates required for the repair process and the function of its players. Additionally, proteins of the DDR can regulate the metabolic flux through the major pathways such as glycolysis, tricarboxylic acid cycle (TCA) and pentose phosphate pathway (PPP) and the production of reactive oxygen species (ROS). This newly discovered connection bears great importance in the biology of cancer and represents a new therapeutic opportunity. Here we describe the nature of the relationship between DDR and metabolism and its potential application in the treatment of cancer. Keywords: DNA repair, metabolism, mitochondria.

Keywords: DNA repair; metabolism; mitochondria

DOI: https://doi.org/10.1080/15384101.2021.1912889

Science. 2021 Apr 22. pii: eabd5491. [Epub ahead of print]

Mitochondrial NADP(H) generation is essential for proline biosynthesis.

Jiajun Zhu, Simon Schwörer, Mirela Berisa, Yeon Ju Kyung, Keun Woo Ryu, Junmei Yi, Xuejun Jiang, Justin R Cross, Craig B Thompson.

The coenzyme nicotinamide adenine dinucleotide phosphate (NADP+) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of NADK2 in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.

DOI: https://doi.org/10.1126/science.abd5491

Eur J Cancer. 2021 Apr 14. pii: S0959-8049(21)00137-4. [Epub ahead of print]149 184-192

Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors.

Shumei Kato, Robert Porter, Ryosuke Okamura, Suzanna Lee, Ori Zelichov, Gabi Tarcic, Michael Vidne, Razelle Kurzrock.

BACKGROUND: RAS variant-related functional impact on the mitogen-activated protein kinase (MAPK) pathway, and correlation between MAPK activation and MAPK/ERK kinase (MEK) inhibitor responsiveness, is not established.
PATIENTS AND METHODS: Of 1,693 tumours sequenced, 576 harboured a RAS alteration; 62 patients received an MEK inhibitor (MEKi) and had RAS mutations that were functionally characterised. We report that RAS mutants have variable levels of MAPK activity, as measured by a functional cell-based assay that quantified MAPK pathway activation after transfection with a variety of RAS mutations.
RESULTS: Patients with tumours harbouring RAS alterations with high versus low MAPK activity who were treated with an MEKi showed significantly longer median progression-free survival (PFS) (5.0 vs. 2.3 months; p = 0.0034) and overall survival (20.0 vs. 5.0 months; p = 0.0146) and a trend towards higher rates of clinical benefit (stable disease ≥6 months or partial/complete remission) (38% versus 15%; p = 0.095) (p-values as per univariate analysis). PFS remained statistically significant after the multivariate analysis (p = 0.003).
CONCLUSIONS: These results support a correlation between RAS-mutant cancers with greater MAPK signalling and PFS after MEKi treatment.

Keywords: Cancer; MAPK activity; MEK inhibitor; RAS

DOI: https://doi.org/10.1016/j.ejca.2021.01.055

Nat Commun. 2021 Apr 22. 12(1): 2383

Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.

Zhiyong Wang, Yusuke Goto, Michael M Allevato, Victoria H Wu, Robert Saddawi-Konefka, Mara Gilardi, Diego Alvarado, Bryan S Yung, Aoife O'Farrell, Alfredo A Molinolo, Umamaheswar Duvvuri, Jennifer R Grandis, Joseph A Califano, Ezra E W Cohen, J Silvio Gutkind.

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.

DOI: https://doi.org/10.1038/s41467-021-22619-w

Nat Cancer. 2021 Mar;2(3): 271-283

The Metabolic Landscape of RAS-Driven Cancers from biology to therapy.

Suman Mukhopadhyay, Matthew G Vander Heiden, Frank McCormick.

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.

Keywords: KRAS; autophagy; cancer therapeutics; chemoresistance; ferroptosis; glutaminolysis; glycolysis; macropinocytosis; metabolism

DOI: https://doi.org/10.1038/s43018-021-00184-x

Redox Biol. 2021 Apr 02. pii: S2213-2317(21)00112-9. [Epub ahead of print] 101964

Redox regulation of the insulin signalling pathway.

Claudia Lennicke, Helena M Cochemé.

The peptide hormone insulin is a key regulator of energy metabolism, proliferation and survival. Binding of insulin to its receptor activates the PI3K/AKT signalling pathway, which mediates fundamental cellular responses. Oxidants, in particular H2O2, have been recognised as insulin-mimetics. Treatment of cells with insulin leads to increased intracellular H2O2 levels affecting the activity of downstream signalling components, thereby amplifying insulin-mediated signal transduction. Specific molecular targets of insulin-stimulated H2O2 include phosphatases and kinases, whose activity can be altered via redox modifications of critical cysteine residues. Over the past decades, several of these redox-sensitive cysteines have been identified and their impact on insulin signalling evaluated. The aim of this review is to summarise the current knowledge on the redox regulation of the insulin signalling pathway.

Keywords: Cysteine post-translational modification; FOXO; H(2)O(2); Insulin signalling; NRF2; ROS; Redox regulation; Type-2 diabetes

DOI: https://doi.org/10.1016/j.redox.2021.101964

J Mol Biol. 2021 Apr 15. pii: S0022-2836(21)00190-X. [Epub ahead of print] 166989

Structural basis of DEPTOR to recognize phosphatidic acid using its tandem DEP domains.

Zhuangfeng Weng, Xinxin Shen, Jiefu Zheng, Huanhuan Liang, Yingfang Liu.

DEP domain containing mTOR-interacting protein (DEPTOR) plays pivotal roles in regulating metabolism, growth, autophagy and apoptosis by functions as an endogenous inhibitor of mTOR signaling pathway. Activated by phosphatidic acid, a second messenger in mTOR signaling, DEPTOR dissociates from mTORC1 complex with unknown mechanism. Here, we present a 1.5 Å resolution crystal structure, which shows that the N-terminal two tandem DEP domains of hDEPTOR fold into a dumbbell-shaped structure, protruding the characteristic β-hairpin arms of DEP domains on each side. An 18 amino acids DDEX motif at the end of DEP2 interacts with DEP1 and stabilizes the structure. Biochemical studies showed that the tandem DEP domains directly interact with phosphatidic acid using two distinct positively charged patches. These results provide insights into mTOR activation upon phosphatidic acid stimulation.

Keywords: Anionic lipid; Crystal structure; DDEX motif; DEPDC6; mTOR

DOI: https://doi.org/10.1016/j.jmb.2021.166989