KRAS: A Druggable Target in Colon Cancer Patients

Negri, Francesca; Bottarelli, Lorena; de’Angelis, Gian Luigi; Gnetti, Letizia

doi:10.3390/ijms23084120

Cited by 27 publications

(6 citation statements)

References 137 publications

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“…Furthermore, the role of lysosomal sequestration in drug accumulation, whether a potential mechanism for tumoral sensitization or cellular resistance that may be overwhelmed by very high dosing [29,30], requires further investigation. KRAS-mutant mCRC urgently needs more (targeted) therapeutic options; patients with these cancers do not respond to the otherwise clinically bene cial strategies blocking the pathway KRAS is involved in signalling [51][52][53]. Although recent work from Fukada et al has shown that harbouring a KRAS-G12V mutation causes osimertinib resistance in NSCLC [54], we show high drug activity in all three KRASmutant mCRC PDTOs.…”

Section: Discussionmentioning

confidence: 52%

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

Iyer¹,

Poel²,

Miggelenbrink³

et al. 2023

Preprint

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Background Despite major interest in tyrosine kinase inhibitors (TKIs) as a treatment option for metastatic colorectal cancer (mCRC), almost all TKIs tested for mCRC fail in early-phase clinical trials. Although showing specific target inhibition at low concentrations, TKIs have a much broader kinase inhibitory potency at higher concentrations. In an attempt to leverage these many additional, low-affinity targets, high-dose regimens that may trigger efficacy are explored. Here, we studied unprecedented drug exposure–response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs). Methods We established patient-derived tumor organoids (PDTOs) from mCRC biopsies and, based on favorable physicochemical and pharmacokinetic properties, selected 3 TKIs (sunitinib, cediranib and osimertinib). Following standard IC50 assessment using continuous dosing with a concentration range, we investigated the cytotoxic antitumor effect of high-dose, short-term (HDST) treatment. Five PDTOs were exposed to 20 µM TKI for 1–24h, washed and given normal medium, and PDTO-outgrowth was determined 1 week later. At exposures of 1, 3 and 6 h, we measured intra-tumoroid TKI concentrations using a clinically validated LC/MS-MS method. PDTO cell death was observed using live-cell microscopy, and quantified by both caspase 3/7 enzyme activity assay and cleaved caspase-3 immunofluorescent staining. Results We show that most PDTOs tested are sensitive to multikinase TKIs sunitinib and cediranib, and all to osimertinib. Furthermore, we demonstrate that high-dose, short-term(HDST) TKI treatment effectively blocks organoid growth. In line with recent clinical data of high-dose sunitinib tumour accumulation, HDST treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. This suggests exposure-dependent cytotoxicity and supports the concept that efficacy is induced by a broad kinase inhibitory spectrum. Mechanistically, HDST osimertinib treatment for just 3 hours induced regulated cell death in treated organoids. Conclusion Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. In addition, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.

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Section: Discussionmentioning

confidence: 52%

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

Iyer¹,

Poel²,

Miggelenbrink³

et al. 2023

Preprint

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“…Finally, in the multi‐omic analysis of different SCS subtypes, we were surprised to find that although the activation degree of KRAS pathway at the transcriptome level was significantly increased in SCS2 subtype compared with other subtypes, the somatic mutation of KRAS was significantly enriched in SCS4 subtype and the PCA score of subtype 1 goblet cell signature in the KRAS mutant group was also significantly higher compared with that in the KRAS wild‐type group. We hypothesized that this result may be due to the presence of other factors that inhibit KRAS signaling activation in the SCS4 subtype [ 36 ]. Therefore, the specific link between KRAS mutation and goblet cell accumulation and differentiation in colon cancer needs to be further examined in future studies.…”

Section: Discussionmentioning

confidence: 99%

Expression pattern of secretory‐cell‐related transcriptional signatures in colon adenocarcinomas defines tumor microenvironment characteristics and correlates with clinical outcomes

Zhou

et al. 2022

Molecular Oncology

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Despite the connection of secretory cells to distinct mucus‐containing colon cancer histological subtypes and the interaction of secretory cells with immune cells in the pathogenesis of intestinal inflammatory diseases, whether the secretory cell signatures are associated with tumor microenvironment (TME) heterogeneity and can aid in colon cancer patient classification have not been investigated. Here, by performing the principal component analysis and consensus clustering analysis, we identified four distinct expression patterns based on secretory cell signatures which were significantly associated with different clinical behaviors, TME landscape, pathway activation, genomic mutations, and DNA methylation characteristics. Subsequently, a ‘SCS score’ model was constructed. The high SCS score indicated a pattern of ‘secretory cell subtype 2’, which was characterized by stromal infiltration and activation, and predicted poor prognosis and low sensitivity to fluorouracil‐based chemotherapy and immunotherapy, but high sensitivity to PI3K catalytic subunit inhibitors. In conclusion, our study comprehensively uncovered the tumor heterogeneity related to secretory cell signature expression patterns. Moreover, the SCS score can supplement routine histopathological assessments to guide personalized therapeutic strategies in colon cancer patients.

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“…The MSI tumor is often accompanied by high immunogenicity and high T-cell in ltration microenvironment [47,48], so immune checkpoint inhibitors (ICIs) are more effective in treating RCC than LCC and RC [49,50]. KRAS is involved in signaling pathways activated by EGFR [51], and mutations of KRAS can lead to tumor resistance to anti-EGFR antibodies [52].…”

Section: Discussionmentioning

confidence: 99%

Metagenomic meta-analysis of the gut microbiome in the different primary locations of colorectal cancer

Luo

Liao

et al. 2022

Preprint

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BACKGROUND Recent studies have found a relationship between gut microbes and the primary location of colorectal cancer (CRC). However, most of these studies had limitations in sample size or sequencing methods. In this study, we collected metagenomic data from three studies and meta-analyzed the microbiological features according to the grouping of right-side colon cancer (RCC), left-side colon cancer (LCC), and rectal cancer (RC). METHODS We first identified confounding factors (except for tumor location) by two-way ANOVA and comparing species diversity. Subsequently, the microbial compositions were compared between different tumor locations. Microbial co-occurrence networks were established based on samples with different tumor locations. A prediction model for primary tumor location was constructed using a random forest algorithm based on microbial abundance features. Finally, tumor location and confounding factors were entered in the MAASLIN2 to identify differential species. Linear discriminant analysis (LDA) also identified the differential species. RESULTS Different study sources and BMI influenced gut microbiome and significantly altered α-diversity and β-diversity, bringing the confounding effect when analyzing gut microbial features in different tumor locations. However, α-diversity and β-diversity of gut microbiome had no significant difference in tumor locations. Species belonging to the Phylum of Actinobacteria, Firmicutes, and Proteobacteria played essential linkages in the three microbial networks, while Bacteroidetes were more critical in the microbial network of RCC. There are both the same hub species and different hub species among the three networks. The random forest classification model performed well in predicting RC (class error = 0.217) but poorly classified the RCC and LCC, with an overall classification error of 0.613. In comparing colon cancer (CC) with RC, MAASLIN2 and LDA identified six species significantly enriched in RC and thirteen in CC. In comparing RCC with LCC, MAASLIN2 identified nine species significantly enriched in RCC and six significantly enriched in LCC. Some of the differential species were reported to be associated with CRC location-related Molecular and immune features. CONCLUSION This study elucidated the relationship between gut microbiome and CRC location and confirmed that RCC, LCC, and RC had different enrich patterns of microbiota.

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KRAS: A Druggable Target in Colon Cancer Patients

Cited by 27 publications

References 137 publications

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

Expression pattern of secretory‐cell‐related transcriptional signatures in colon adenocarcinomas defines tumor microenvironment characteristics and correlates with clinical outcomes

Metagenomic meta-analysis of the gut microbiome in the different primary locations of colorectal cancer

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