bims-pimaco 2021-12-26 papers

Molecules. 2021 Dec 14. pii: 7561. [Epub ahead of print]26(24):

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy.

Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.

Keywords: PI3K-mTOR; RAS effectors; RAS-driven cancers; Raf/MEK/Erk

DOI: https://doi.org/10.3390/molecules26247561

Int J Mol Sci. 2021 Dec 07. pii: 13193. [Epub ahead of print]22(24):

Past and Future Strategies to Inhibit Membrane Localization of the KRAS Oncogene.

Malak Haidar, Patrick Jacquemin.

KRAS is one of the most studied oncogenes. It is well known that KRAS undergoes post-translational modifications at its C-terminal end. These modifications are essential for its membrane location and activity. Despite significant efforts made in the past three decades to target the mechanisms involved in its membrane localization, no therapies have been approved and taken into the clinic. However, many studies have recently reintroduced interest in the development of KRAS inhibitors, either by directly targeting KRAS or indirectly through the inhibition of critical steps involved in post-translational KRAS modifications. In this review, we summarize the approaches that have been applied over the years to inhibit the membrane localization of KRAS in cancer and propose a new anti-KRAS strategy that could be used in clinic.

Keywords: KRAS; RAS; cancer; plasma membrane

DOI: https://doi.org/10.3390/ijms222413193

Cells. 2021 Dec 05. pii: 3423. [Epub ahead of print]10(12):

The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene.

Jose Antonio Ma G Garrido, Krizelle Mae M Alcantara, Joshua Miguel C Danac, Fidel Emmanuel C Serrano, Eva Maria Cutiongco-de la Paz, Reynaldo L Garcia.

Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K-Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors.

Keywords: EGFR pathway; PTEN; colorectal cancer; tumor suppressor

DOI: https://doi.org/10.3390/cells10123423

Elife. 2021 Dec 23. pii: e72593. [Epub ahead of print]10

Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.

Dylan Gerard Ryan, Ming Yang, Hiran A Prag, Giovanny Rodriguez Blanco, Efterpi Nikitopoulou, Marc Segarra-Mondejar, Christopher A Powell, Tim Young, Nils Burger, Jan Lj Miljkovic, Michal Minczuk, Michael P Murphy, Alex von Kriegsheim, Christian Frezza.

The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.

Keywords: biochemistry; cell biology; chemical biology; mouse

DOI: https://doi.org/10.7554/eLife.72593