bims-pimaco 2021-11-14 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2021–11–14
ten papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

PIK3CA mutation affects the proliferation of colorectal cancer cells through the PI3K-MEK/PDK1-GPT2 pathway.
Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer.
Diverse alterations associated with resistance to KRAS(G12C) inhibition.
Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition.
Age-dependent prognostic value of KRAS mutation in metastatic colorectal cancer.
Exploring Better Strategies for RAS Mutation-Associated EGFR-Targeted Resistance in Colorectal Cancer: From the Perspective of Cancer Community Ecology.
Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling.
MTOR/4EBP1 signaling and MMR status in colorectal cancer: New correlations and arising perspectives.
Overview of the regulation of the class IA PI3K/AKT pathway by SUMO.

Oncol Rep. 2022 Jan;pii: 11. [Epub ahead of print]47(1):

PIK3CA mutation affects the proliferation of colorectal cancer cells through the PI3K-MEK/PDK1-GPT2 pathway.

Wenli Chen, Guangli Dai, Yike Qian, Lian Wen, Xueqing He, Hui Liu, Yunxing Gao, Xingli Tang, Bohan Dong.

  The phosphatidylinositol‑3‑kinase catalytic subunit α (PIK3CA) gene is mutated in numerous human cancers. This mutation promotes the proliferation of tumor cells; however, the underlying mechanism is still not clear. In the present study, it was revealed that the PIK3CA mutation in colorectal cancer (CRC) HCT116 (MUT) rendered the cells more dependent on glutamine by regulating the glutamic‑pyruvate transaminase 2 (GPT2). The dependence of glutamine increased the proliferation of cells in a normal environment and resistance to a suboptimal environment. Further study revealed that the mutated PIK3CA could regulate GPT2 expression not only through signal transduction molecule 3‑phosphoinositide‑dependent kinase (PDK1) but also through mitogen‑activated protein kinase (MEK) molecules. In HCT116 cells, MEK inhibitor treatment could reduce the expression of GPT2 signaling molecules, thereby inhibiting the proliferation of CRC cells. A new signal transduction pathway, the PI3K/MEK/GPT2 pathway was identified. Based on these findings, MEK and PDK1 inhibitors were combined to inhibit the aforementioned pathway. It was revealed that the combined application of MEK and PDK1 inhibitors could promisingly inhibit the proliferation of MUT compared with the application of PI3K inhibitors, PDK1 inhibitors, or MEK inhibitors alone. In vivo, MEK inhibitors alone and combined inhibitors had stronger tumor‑suppressing effects. There was no significant difference between the PDK1‑inhibitor group and normal group in vivo. Thus, these results indicated that mutated PI3K affected GPT2 mediated by the MEK/PDK1 dual pathway, and that the PI3K/MEK/GPT2 pathway was more important in vivo. Inhibiting MEK and PDK1 concurrently could effectively inhibit the proliferation of CRC cells. Targeting the MEK and PDK1 signaling pathway may provide a novel strategy for the treatment of PIK3CA‑mutated CRC.

Keywords:  colorectal cancer; glutamine transaminase 2; mitogen‑activated protein kinase; mutation; phosphatidylinositol‑3‑kinase catalytic subunit α; proliferation

DOI:  https://doi.org/10.3892/or.2021.8222
Mol Cancer. 2021 Nov 06. 20(1): 143

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer.

Gongmin Zhu, Lijiao Pei, Hongwei Xia, Qiulin Tang, Feng Bi.

  Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

Keywords:  Colorectal cancer; Combination therapy; G12C; KRAS; Prognosis; Targeted therapy

DOI:  https://doi.org/10.1186/s12943-021-01441-4
Nature. 2021 Nov 10.

Diverse alterations associated with resistance to KRAS(G12C) inhibition.

Yulei Zhao, Yonina R Murciano-Goroff, Jenny Y Xue, Agnes Ang, Jessica Lucas, Trang T Mai, Arnaud F Da Cruz Paula, Anne Y Saiki, Deanna Mohn, Pragathi Achanta, Ann E Sisk, Kanika S Arora, Rohan S Roy, Dongsung Kim, Chuanchuan Li, Lee P Lim, Mark Li, Amber Bahr, Brian R Loomis, Elisa de Stanchina, Jorge S Reis-Filho, Britta Weigelt, Michael Berger, Gregory Riely, Kathryn C Arbour, J Russell Lipford, Bob T Li, Piro Lito.

Inactive state-selective KRAS(G12C) inhibitors1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

DOI: https://doi.org/10.1038/s41586-021-04065-2
J Proteome Res. 2021 Nov 09.

Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition.

Xu-Dong Wang, Chiho Kim, Yajie Zhang, Smita Rindhe, Melanie H Cobb, Yonghao Yu.

  Although targeted MAPK pathway inhibition has achieved remarkable patient responses in many cancers, the development of resistance has remained a critical challenge. Adaptive tumor response underlies the drug resistance. Furthermore, such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies. Here, we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted MAPK signaling inhibition in melanoma leads to a profound remodeling of the pTyr proteome. Intriguingly, altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found an accumulation of intracellular cholesterol in melanoma cells (with BRAFV600E mutations) and non-small cell lung cancer cells (with KRASG12C mutations) treated with MAPK and KRASG12C inhibitors, respectively. Importantly, depletion of cholesterol not only prevents the feedback activation of pTyr signaling but also enhances the cytotoxic effects of MAPK pathway inhibitors, both in vitro and in vivo. Together, our findings suggest that cholesterol contributes to the tumor adaptive response upon targeted MAPK pathway inhibitors. These results also suggest that MAPK pathway inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling.

Keywords:  RTK; adaptive resistance; cholesterol; combination treatment; phosphoproteomic

DOI:  https://doi.org/10.1021/acs.jproteome.1c00550
Future Oncol. 2021 Nov 11.

Age-dependent prognostic value of KRAS mutation in metastatic colorectal cancer.

Muhammet Ozer, Suleyman Yasin Goksu, Nina Niu Sanford, Chul Ahn, Muhammad Shaalan Beg, Syed Mohammad Ali Kazmi.

  Background: The age-dependent prognostic impact of KRAS status in metastatic colorectal cancer (mCRC) is unknown. Materials & Methods: We used the National Cancer Database to evaluate the survival by KRAS status for age-groups <50, 50-69 and ≥70, adjusting for relevant patient and tumor characteristics. Results: mCRC patients (n = 26,095; 33.5%) had KRAS status reported, and 11,338 of these patients (43.4%) had mutations in the KRAS gene. Patients with KRAS mutations had worse overall survival than wild-type KRAS patients. In age-groups <50 years (23 vs 29 months; p < 0.001) and 50-69 (21 vs 23.4 months; p < 0.001), KRAS mutations were significantly associated with worse survival, whereas in the ≥70-year age-group, there was no significant association (14 vs 14 months; p = 0.34). Conclusion: We conclude that the age of patients influences the prognostic value of KRAS mutation in metastatic colorectal cancer.

Keywords:  KRAS; age of onset; colorectal neoplasms; database; metastasis

DOI:  https://doi.org/10.2217/fon-2021-0650
Front Oncol. 2021 ;11 754220

Exploring Better Strategies for RAS Mutation-Associated EGFR-Targeted Resistance in Colorectal Cancer: From the Perspective of Cancer Community Ecology.

Xiaojie Wang, Wenchuan Wu, Zhifang Zheng, Pan Chi.

  RAS is the most common mutated gene in colorectal cancer (CRC), and its occurrence is associated with primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) blockade. Cancer community ecology, such as the competitive exclusion principle, is a valuable focus and would contribute to the understanding of drug resistance. We have presented several articles on RAS mutant clonal evolution monitoring during anti-EGFR treatment in CRC. In these articles, the availability of serially collected samples provided a unique opportunity to model the tumor evolutionary process from the perspective of cancer community ecology in those patients upon treatment. In this perspective article, we presented a theoretical basis and evidence from several experimental or phase II clinical trials for the contemporary application of ecological mechanisms in CRC treatment. In general, a reduction in targetable RAS wild-type cells to a maximum tolerated extent, such as continuous treatment, might lead to the competitive release of inextirpable RAS mutant cells and cancer progression. A full understanding of subclonal competition might be beneficial in managing CRC. Several ecological strategies, including anti-EGFR treatment reintroduced at an appropriate point of time for RAS mutant patients, intermittent treatment instead of continuous treatment, the appropriate sequence of nonselective targeted therapy, and combination therapy, were proposed.

Keywords:  EGFR; RAS; cancer community ecology; colorectal cancer; resistance

DOI:  https://doi.org/10.3389/fonc.2021.754220
PLoS Genet. 2021 Nov;17(11): e1009876

Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.

Ralitsa R Madsen, Emily C Erickson, Oscar M Rueda, Xavier Robin, Carlos Caldas, Alex Toker, Robert K Semple, Bart Vanhaesebroeck.

A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a "biphasic" relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation.

DOI: https://doi.org/10.1371/journal.pgen.1009876
J Mol Cell Biol. 2021 Nov 09. pii: mjab073. [Epub ahead of print]

The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling.

Junsik M Lee, Renyan Liu, Sang Won Park.

  Bromodomain-containing protein 7 (BRD7) has been shown to interact with the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85, in the insulin signaling pathway. Here, we show that upregulation of hepatic BRD7 improves glucose homeostasis even in the absence of either p85 isoform, p85α or p85β. However, BRD7 leads to differential activation of downstream effector proteins in the insulin signaling pathway depending on which isoform of p85 is present. In the presence of only p85α, BRD7 overexpression increases phosphorylation of insulin receptor upon insulin stimulation, without increasing the recruitment of p85 to insulin receptor substrate. Overexpression of BRD7 also increases activation of Akt in response to insulin but does not affect basal phosphorylation levels of Akt. Meanwhile, the phosphorylation of glycogen synthase kinase 3β (GSK3β) is increased by overexpression of BRD7. On the other hand, in the presence of only p85β, BRD7 overexpression does not affect phosphorylation levels of insulin receptor, and Akt phosphorylation is not affected by insulin stimulation following BRD7 upregulation. However, BRD7 overexpression leads to increased basal phosphorylation levels of Akt and GSK3β. These data demonstrate that BRD7's action on glucose homeostasis does not require the presence of both p85 isoforms, and p85α and p85β have unique roles in insulin signaling in the liver.

Keywords:  Akt; BRD7; PI3K; insulin signaling

DOI:  https://doi.org/10.1093/jmcb/mjab073
Pathol Res Pract. 2021 Oct 15. pii: S0344-0338(21)00316-2. [Epub ahead of print]228 153655

MTOR/4EBP1 signaling and MMR status in colorectal cancer: New correlations and arising perspectives.

Dionysia N Zouki, Ioanna Giannopoulou, Paraskevi Th Alexandrou, Eleni A Karatrasoglou, Georgios Pilichos, Konstantinos Stamopoulos, Theodore Kanellis, Eirini Roupou, Angelica A Saetta, Irini Thymara, Nikolaos Kavantzas, Andreas C Lazaris.

  This is the first study aiming to investigate mTOR signaling and its relation to mismatch repair status (MMR status) in colorectal cancer (CRC). MMR status and the phosphorylated proteins, pmTOR and p4EBP1, have been immunohistochemically analyzed in 108 formalin-fixed, paraffin-embedded CRC specimens. The correlations between them and with clinicopathological data, MAPK pathway (KRAS, NRAS, BRAF) as well as their impact on patients' overall survival have been statistically analyzed. Our results indicated that positive pmTOR expression was significantly associated with KRAS mutations (p = 0.004). From multivariate survival analysis, only p4EBP1 expression emerged as independent adverse prognostic factor for overall survival (HR, 3.322; 95%CI, 1.110-9.945; p = 0.032). Furthermore, MMR deficient carcinomas tend to express low p4EBP1 protein levels (p = 0.002). A survival analysis stratified by MMR status and p4EBP1 expression, showed that MMR proficient tumours with high p4EBP1 expression had the worst overall survival compared with the other examined subgroups (p = 0.019). In conclusion, MAPK and PI3k/Akt pathways seem to be simultaneously overactivated in CRC. P4EBP1 could be used as a prognostic biomarker. By further analyzing the significant association between MMR status and p4EBP1 expression, we suggest that MMR deficient tumours could represent a subpopulation most likely to derive treatment benefit from mTOR inhibition.

Keywords:  MMR status; MTOR targeted therapy; P4EBP1; PmTOR; Prognosis

DOI:  https://doi.org/10.1016/j.prp.2021.153655
Semin Cell Dev Biol. 2021 Nov 06. pii: S1084-9521(21)00275-5. [Epub ahead of print]

Overview of the regulation of the class IA PI3K/AKT pathway by SUMO.

Santiago Vidal, Yanis Hichem Bouzaher, Ahmed El Motiam, Rocío Seoane, Carmen Rivas.

  The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is a major regulator of metabolism, migration, survival, proliferation, and antiviral immunity. Both an overactivation and an inhibition of the PI3K/AKT pathway are related to different pathologies. Activation of this signaling pathway is tightly controlled through a multistep process and its deregulation can be associated with aberrant post-translational modifications including SUMOylation. Here, we review the complex modulation of the PI3K/AKT pathway by SUMOylation and we discuss its putative involvement in human disease.

Keywords:  AKT; PI3K; PTEN; SUMO; p110; p85

DOI:  https://doi.org/10.1016/j.semcdb.2021.10.012