bims-pimaco 2022-06-19 papers

Front Oncol. 2022 ;12 880552

Statin Treatment as a Targeted Therapy for APC-Mutated Colorectal Cancer.

Hannah Shailes, Wai Yiu Tse, Marta O Freitas, Andrew Silver, Sarah A Martin.

Background: Mutations in the tumor suppressor gene Adenomatous Polyposis Coli (APC) are found in 80% of sporadic colorectal cancer (CRC) tumors and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP).
Methods: To identify novel therapeutic strategies for the treatment of APC mutated CRC, we generated a drug screening platform that incorporates a human cellular model of APC mutant CRC using CRISPR-cas9 gene editing and performed an FDA-approved drug screen targeting over 1000 compounds.
Results: We have identified the group of HMG-CoA Reductase (HMGCR) inhibitors known as statins, which cause a significantly greater loss in cell viability in the APC mutated cell lines and in in vivo APC mutated patient derived xenograft (PDX) models, compared to wild-type APC cells. Mechanistically, our data reveals this new synthetic lethal relationship is a consequence of decreased Wnt signalling and, ultimately, a reduction in the level of expression of the anti-apoptotic protein Survivin, upon statin treatment in the APC-mutant cells only. This mechanism acts via a Rac1 mediated control of beta-catenin.
Conclusion: Significantly, we have identified a novel synthetic lethal dependence between APC mutations and statin treatment, which could potentially be exploited for the treatment of APC mutated cancers.

Keywords: APC; biomarker; colorectal (colon) cancer; personalized medicine; statin (HMG-CoA reductase inhibitor); synthetic lethality

DOI: https://doi.org/10.3389/fonc.2022.880552

Ther Adv Med Oncol. 2022 ;14 17588359221097940

Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas.

Meredith Li, Faeze Keshavarz-Rahaghi, Gale Ladua, Lucas Swanson, Caroline Speers, Daniel J Renouf, Howard J Lim, Janine M Davies, Sharlene Gill, Heather C Stuart, Stephen Yip, Jonathan M Loree.

Introduction: In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations.
Patients and Methods: This retrospective review evaluated patients in British Columbia, Canada with mCRC and RAS testing performed between 1 January 2016 and 31 December 2018. Sequencing information from The Cancer Genome Analysis (TCGA) was also obtained and analysed.
Results: Age at diagnosis, sex, anatomic location and stage at diagnosis did not differ by RAS mutation type. Progression free survival on first chemotherapy for patients with metastatic KRAS G12C tumours was 11 months. Median overall survival did not differ by RAS mutation type but was worse for both KRAS G12C (27 months) and non-G12C alterations (29 months) than wildtype (43 months) (p = 0.01). Within the TCGA, there was no differential gene expression between KRAS G12C and other RAS mutations. However, eight genes with copy number differences between the G12C and non-G12C RAS mutant groups were identified after adjusting for multiple comparisons (FITM2, PDRG1, POFUT1, ERGIC3, EDEM2, PIGU, MANBAL and PXMP4). We also noted that other RAS mutant mCRCs had a higher tumour mutation burden than those with KRAS G12C mutations (median 3.05 vs 2.06 muts/Mb, p = 4.2e-3) and that KRAS G12C/other RAS had differing consensus molecular subtype distribution from wildtype colorectal cancer (CRC) (p < 0.0001) but not each other (p = 0.14).
Conclusion: KRAS G12C tumours have similar clinical presentation to other RAS mutant tumours, however, are associated with differential copy number alterations.

Keywords: RAS; cancer; colon; metastatic; rectal; signalling

DOI: https://doi.org/10.1177/17588359221097940

Cancer Res. 2022 Jun 15. 82(12): 2216-2218

PI3King the Environment for Growth: PI3K Activation Drives Transcriptome Changes That Support Oncogenic Growth.

Sally E Claridge, Benjamin D Hopkins.

PI3K signaling plays an integral role in cells, coordinating the necessary alterations in cellular metabolism and programs to support survival and proliferation. In the first genome-wide analysis of alternative splicing in PIK3CA-mutant breast cancer, Ladewig and colleagues show that activating mutations in PIK3CA alter the use of known exons and splice junctions, leading to changes in gene expression and transcription factor activity that promote an oncogenic phenotype. Their work reveals a novel mechanism underlying the functional impact of PI3K signal activation in the context of breast cancer, where PIK3CA mutations are common and PI3K inhibitors are part of the standard of care. Their studies uncover a feedforward mechanism by which PI3K signaling enables a shift in the spectrum of translated splice variants as another method through which the PI3K pathway has evolved to regulate its own activity, thereby modifying the cellular response to upstream activation based on the signaling that has come before. These findings have profound implications for understanding the evolution of the PI3K pathway and the rewiring of cells in response to prolonged or repeated signal activation. See related article by Ladewig et al., p. 2269.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1466

Mol Syst Biol. 2022 Jun;18(6): e10670

Optogenetic actuator - ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics.

Coralie Dessauges, Jan Mikelson, Maciej Dobrzyński, Marc-Antoine Jacques, Agne Frismantiene, Paolo Armando Gagliardi, Mustafa Khammash, Olivier Pertz.

Combining single-cell measurements of ERK activity dynamics with perturbations provides insights into the MAPK network topology. We built circuits consisting of an optogenetic actuator to activate MAPK signaling and an ERK biosensor to measure single-cell ERK dynamics. This allowed us to conduct RNAi screens to investigate the role of 50 MAPK proteins in ERK dynamics. We found that the MAPK network is robust against most node perturbations. We observed that the ERK-RAF and the ERK-RSK2-SOS negative feedback operate simultaneously to regulate ERK dynamics. Bypassing the RSK2-mediated feedback, either by direct optogenetic activation of RAS, or by RSK2 perturbation, sensitized ERK dynamics to further perturbations. Similarly, targeting this feedback in a human ErbB2-dependent oncogenic signaling model increased the efficiency of a MEK inhibitor. The RSK2-mediated feedback is thus important for the ability of the MAPK network to produce consistent ERK outputs, and its perturbation can enhance the efficiency of MAPK inhibitors.

Keywords: ERK dynamics; MAPK network; optogenetics; signaling robustness; single-cell biology

DOI: https://doi.org/10.15252/msb.202110670

J Biol Chem. 2022 Jun 10. pii: S0021-9258(22)00562-2. [Epub ahead of print] 102121

A novel anti-proliferative PKCα-Ras-ERK signaling axis in intestinal epithelial cells.

Navneet Kaur, Michelle Lum, Robert E Lewis, Adrian R Black, Jennifer D Black.

We have previously shown that the serine/threonine kinase PKCα triggers MAPK/ERK kinase (MEK)-dependent G1→S cell cycle arrest in intestinal epithelial cells, characterized by downregulation of cyclin D1 and inhibitor of DNA-binding protein 1 (Id1) and upregulation of the cyclin-dependent kinase inhibitor p21Cip1. Here, we use pharmacological inhibitors, genetic approaches, siRNA-mediated knockdown, and immunoprecipitation to further characterize anti-proliferative ERK signaling in intestinal cells. We show that PKCα signaling intersects the Ras-Raf-MEK-ERK kinase cascade at the level of Ras small GTPases, and that anti-proliferative effects of PKCα require active Ras, Raf, MEK and ERK, core ERK pathway components that are also essential for pro-proliferative ERK signaling induced by epidermal growth factor (EGF). However, PKCα-induced anti-proliferative signaling differs from EGF signaling in that it is independent of the Ras guanine nucleotide exchange factors (Ras-GEFs), SOS1/2, and involves prolonged rather than transient ERK activation. PKCα forms complexes with A-Raf, B-Raf and C-Raf that dissociate upon pathway activation, and all three Raf isoforms can mediate PKCα-induced anti-proliferative effects. At least two PKCα-ERK pathways that collaborate to promote growth arrest were identified: one pathway requiring the Ras-GEF, RasGRP3, and H-Ras, leads to p21Cip1 upregulation, while additional pathway(s) mediate PKCα-induced cyclin D1 and Id1 downregulation. PKCα also induces ERK-dependent SOS1 phosphorylation, indicating possible negative crosstalk between anti-proliferative and growth-promoting ERK signaling. Importantly, the spatio-temporal activation of PKCα and ERK in the intestinal epithelium in vivo supports the physiological relevance of these pathways and highlights the importance of anti-proliferative ERK signaling to tissue homeostasis in the intestine.

Keywords: EGF; ERK; H-Ras protein; Id1; PKCα; Raf kinase; RasGRP3; cyclin D1; growth arrest; p21(Cip1)

DOI: https://doi.org/10.1016/j.jbc.2022.102121