bims-pimaco 2022-06-26 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2022‒06‒26
eight papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research

Fibroblast-Induced Paradoxical PI3K Pathway Activation in PTEN-Competent Colorectal Cancer: Implications for Therapeutic PI3K/mTOR Inhibition.
KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy.
Reciprocal regulation of Daxx and PIK3CA promotes colorectal cancer cell growth.
Combination of mTOR inhibitor PP242 and AMPK activator metformin exerts enhanced inhibitory effects on colorectal carcinoma cells in vitro by blocking multiple kinase pathways.
The central role of mTORC1 in amino acid sensing.
A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer.
Synthetic Vulnerabilities in the KRAS Pathway.
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.

Front Oncol. 2022 ;12 862806

Fibroblast-Induced Paradoxical PI3K Pathway Activation in PTEN-Competent Colorectal Cancer: Implications for Therapeutic PI3K/mTOR Inhibition.

Fabiana Conciatori, Erica Salvati, Ludovica Ciuffreda, Senji Shirasawa, Italia Falcone, Francesco Cognetti, Gianluigi Ferretti, Massimo Zeuli, Donatella Del Bufalo, Chiara Bazzichetto, Michele Milella.

  Purpose: Tumor-microenvironment interactions are important determinants of drug resistance in colorectal cancer (CRC). We, therefore, set out to understand how interactions between genetically characterized CRC cells and stromal fibroblasts might influence response to molecularly targeted inhibitors.Techniques: Sensitivity to PI3K/AKT/mTOR pathway inhibitors of CRC cell lines, with known genetic background, was investigated under different culture conditions [serum-free medium, fibroblasts' conditioned medium (CM), direct co-culture]. Molecular pathway activation was monitored using Western Blot analysis. Immunoprecipitation was used to detect specific mTOR complex activation. Immunofluorescence was used to analyze cellular PTEN distribution, while different mutant PTEN plasmids were used to map the observed function to specific PTEN protein domains.
Results: Exposure to fibroblast-CM resulted in increased growth-inhibitory response to double PI3K/mTOR inhibitors in PTEN-competent CRC cell lines harboring KRAS and PI3K mutations. Such functional effect was attributable to fibroblast-CM induced paradoxical PI3K/mTORC1 pathway activation, occurring in the presence of a functional PTEN protein. At a molecular level, fibroblast-CM induced C-tail phosphorylation and cytoplasmic redistribution of the PTEN protein, thereby impairing its lipid phosphatase function and favored the formation of active, RAPTOR-containing, mTORC1 complexes. However, PTEN's lipid phosphatase function appeared to be dispensable, while complex protein-protein interactions, also involving PTEN/mTOR co-localization and subcellular distribution, were crucial for both mTORC1 activation and sensitivity to double PI3K/mTOR inhibitors.
Data Interpretation: Microenvironmental cues, in particular soluble factors produced by stromal fibroblasts, profoundly influence PI3K pathway signaling and functional response to specific inhibitors in CRC cells, depending on their mutational background and PTEN status.

Keywords:  CRC; PI3K signaling; PTEN; fibroblasts; soluble factors

DOI:  https://doi.org/10.3389/fonc.2022.862806
Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00779-3. [Epub ahead of print]39(12): 110993

KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy.

Meagan B Ryan, Oluwadara Coker, Alexey Sorokin, Katerina Fella, Haley Barnes, Edmond Wong, Preeti Kanikarla, Fengqin Gao, Youyan Zhang, Lian Zhou, Scott Kopetz, Ryan B Corcoran.

  Although KRAS has long been considered undruggable, direct KRASG12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type RAS, as opposed to a shift in KRASG12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRASG12C-independent manner. Moreover, multiple receptor tyrosine kinases (RTKs) can drive feedback reactivation, potentially necessitating targeting of convergent signaling nodes for more universal efficacy. Even in colorectal cancer, where feedback is thought to be primarily epidermal growth factor receptor (EGFR)-mediated, alternative RTKs drive pathway reactivation and limit efficacy, but convergent upstream or downstream signal blockade can enhance activity. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting KRAS.

Keywords:  CP: Cancer; KRAS; KRASG12C; adagrasib; adaptive resistance; sotorasib

DOI:  https://doi.org/10.1016/j.celrep.2022.110993
Cell Mol Life Sci. 2022 Jun 19. 79(7): 367

Reciprocal regulation of Daxx and PIK3CA promotes colorectal cancer cell growth.

Yen-Sung Huang, Chang-Chieh Wu, Che-Chang Chang, Shiu-Feng Huang, Hong-Yi Kuo, Hsiu-Ming Shih.

  Upregulation of death-domain-associated protein (Daxx) is strongly associated with diverse cancer types. Among these, the clinicopathological significance and molecular mechanisms of Daxx overexpression in colorectal cancer (CRC) remain unknown. Here, we showed that Daxx expression was increased in both clinical CRC samples and CRC cell lines. Daxx knockdown significantly reduced proliferation activity in CRC cells and tumor growth in a xenograft model. Further studies revealed that Daxx expression could be attenuated by either treatment with the PIK3CA inhibitor PIK-75 or PIK3CA depletion in CRC cells. Conversely, expression of PIK3CA constitutively active mutants could increase Daxx expression. These data suggest that PIK3CA positively regulates Daxx expression. Consistently, the expression levels of PIK3CA and Daxx were positively correlated in sporadic CRC samples. Interestingly, Daxx knockdown or overexpression yielded decreased or increased levels of PIK3CA, respectively, in CRC cells. We further demonstrated that Daxx activates the promoter activity and expression of PIK3CA. Altogether, our results identify a mechanistic pathway of Daxx overexpression in CRC and suggest a reciprocal regulation between Daxx and PIK3CA for CRC cell growth.

Keywords:  AKT; CRC; PI3K inhibitors; PIK3CA; p110α

DOI:  https://doi.org/10.1007/s00018-022-04399-8
J Chemother. 2022 Jun 22. 1-11

Combination of mTOR inhibitor PP242 and AMPK activator metformin exerts enhanced inhibitory effects on colorectal carcinoma cells in vitro by blocking multiple kinase pathways.

Cuicui Sun, Xiaoyan Yang, Zhi Jin, Zuhua Gao.

  The second-generation mammalian target of rapamycin (mTOR) inhibitor PP242 has demonstrated limited success in some rapamycin-insensitive tumours. We examined the therapeutic potential of combining PP242 with adenosine 50- monophosphate-activated protein kinase (AMPK) activator metformin, using a panel of colorectal carcinoma (CRC) cell lines. We found that the PP242 and metformin combination enhanced the suppression of CRC cell proliferation, colony formation, and cancer cell apoptosis induction. The effect of this combination was observed on AMPK phosphorylation. Western blotting showed that PP242 inhibited mTORC1 activation, as indicated by the reduced expression of its major substrate p-S6K1 and the partially reduced phosphorylation of eIF4E-binding protein 1 (4E-BP1). The inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT Ser473) was transient and occurred in the first few hours of PP242 treatment; metformin exposure decreased the PP242 activity, counteracting AKT activation. We further demonstrated that this was related to direct AMPK-mediated phosphorylation of IRS-1 at Ser789. Thus, the combination of PP242 and metformin completely blocked the activity of both mTORC1 and mTORC2 kinase. This study suggests that this combination could be a more effective strategy for the treatment of CRC.

Keywords:  AMPK activator; PP242; colorectal cancer; combination therapy; mTOR inhibitor; metformin

DOI:  https://doi.org/10.1080/1120009X.2022.2091122
Cancer Res. 2022 Jun 24. pii: canres.4403.2021. [Epub ahead of print]

The central role of mTORC1 in amino acid sensing.

Shusheng Yue, Guanya Li, Shanping He, Tingting Li.

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth that controls cell homeostasis in response to nutrients, growth factors, and other environmental cues. Recent studies have emphasized the importance of lysosomes as a hub for nutrient sensing, especially amino acid sensing by mTORC1. This review highlights recent advances in understanding the amino acid-mTORC1 signaling axis and the role of mTORC1 in cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-4403
Clin Colorectal Cancer. 2022 May 23. pii: S1533-0028(22)00064-0. [Epub ahead of print]

A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer.

Jeremy Chuang, Jun Gong, Sierra Min Li, Chongkai Wang, Marwan Fakih.

  PURPOSE: We conducted a phase I study to evaluate the maximum tolerated dose (MTD), safety, and efficacy of trametinib in combination with TAS-102 in patients with chemotherapy-refractory KRAS-mutant, wild-type PIK3CA/PTEN metastatic colorectal cancer (mCRC).METHODS: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with chemorefractory mCRC without priorTAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. Primary endpoint was evaluation of MTD.
RESULTS: 25 eligible patients were enrolled in this study. During the dose de-escalation phase, no dose-limiting toxicities (DLT) were observed at the full doses of trametinib/TAS-102 and the MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1 to5 and days 8 to12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was two months (95% confidence interval [CI] 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%).
CONCLUSIONS: Trametinib in combination with TAS-102 demonstrated a manageable safety profile. However, this combination did not achieve meaningful clinical benefit in patients with RAS-mutated PIK3CA and PTEN wild-type refractory mCRC.
CLINICAL TRIAL INFORMATION: NCT03317119.

Keywords:  Metastatic colorectal cancer,Refractory disease, TAS-102; Trametinib

DOI:  https://doi.org/10.1016/j.clcc.2022.05.004
Cancers (Basel). 2022 Jun 08. pii: 2837. [Epub ahead of print]14(12):

Synthetic Vulnerabilities in the KRAS Pathway.

Marta Roman, Elizabeth Hwang, E Alejandro Sweet-Cordero.

  Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.

Keywords:  KRAS; cancer; synthetic lethality

DOI:  https://doi.org/10.3390/cancers14122837
Nat Metab. 2022 Jun 23.

Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.

Zhaoqi Li, Brian W Ji, Purushottam D Dixit, Konstantine Tchourine, Evan C Lien, Aaron M Hosios, Keene L Abbott, Justine C Rutter, Anna M Westermark, Elizabeth F Gorodetsky, Lucas B Sullivan, Matthew G Vander Heiden, Dennis Vitkup.

Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.

DOI: https://doi.org/10.1038/s42255-022-00588-8