Inhibition Of Colorectal Cancer Research Articles

Efficacy and safety of immune checkpoint inhibitors in colorectal cancer: a systematic review and meta-analysis

Background and objectiveImmune checkpoint inhibitor (ICI) therapies have shown promising prospects in colorectal cancer (CRC) immunotherapy; many clinical trials have been carried out. In this study, we sought to evaluate the efficacy and safety of ICI therapies in CRC by presenting a meta-analysis of relevant studies.MethodsDatabases including PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for studies concerning the efficacy and safety of ICI in colorectal cancer. The reported odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs), and TRAEs ≥ 3 in the included studies were analyzed by fixed effects/random effects models.ResultsThree studies involving 667 patients with colorectal cancer were included in our meta-analysis. No significant difference between the immune checkpoint inhibitor therapies and conventional therapies in OS (WMD = 0.73, 95% CI − 3.09, 4.54; p = 0.71), in ORR (OR = 1.54, 95% CI 0.98, 2.40; p = 0.06), and in DCR (OR = 0.97, 95% CI 0.36, 2.61; p = 0.95). The median PFS of the ICI therapy group was shorter than that of the conventional therapy group (WMD = − 0.10, 95% CI − 0.18, − 0.02; p = 0.02). At the same time, we also could not find a significant difference between the immune checkpoint inhibitor therapies and conventional therapies in TRAEs (OR = 1.56, 95% CI 0.11, 22.09; p = 0.74) and in TRAEs ≥ 3 (OR = 0.94, 95% CI 0.16, 5.65; p = 0.95).ConclusionImmune checkpoint inhibitor therapies could not improve all survival endpoints to advanced or metastatic colorectal cancer patients. Whether immune checkpoint inhibitors should be the first choice of therapies for colorectal cancer patients with undetermined microsatellite status or not able to determine microsatellite status needs more related studies to prove.

Immune checkpoint inhibitors in colorectal cancer: dream and reality

A major breakthrough in medical oncology was the discovery of immune checkpoints and the development of immune checkpoint inhibitors. Neoadjuvant checkpoint inhibition is a promising new approach to manage some melanomas and lung cancers, and is also being explored in other cancers.1 This approach relies on the ability of neoadjuvant immune checkpoint inhibitors to induce T-cell expansion at early stages of cancer when T-cell function is less impaired, and it has the potential to reduce tumour size before surgery.

The Expression of Immune Checkpoint Receptors and Ligands in the Colorectal Cancer Tumor Microenvironment.

The limited efficacy of immune checkpoint inhibitors in colorectal cancer (CRC) is likely due to immunosuppressive mechanisms including T cell exhaustion caused by inhibitory immune checkpoints in the tumor microenvironment. We investigated the expression status of the inhibitory immune checkpoint receptors on tumor-infiltrating T cells and their ligands on tumor cells by flow cytometry and immunohistochemistry, using surgically-resected specimens of CRC. Flow cytometry analysis indicated that TIM-3, TIGIT, and PD-1 were expressed on tumor-infiltrating CD4+ (8.3%, 56.0%, 26.1%) and CD8+ T cells (8.2%, 51.6%, 23.5%), and CRC cells abundantly expressed PD-L1, CEACAM-1, and CD155 (2.2%, 77.0%, 46.8%). Immunohistochemical analysis revealed that the tumor proportional score of PD-L1, CEACAM-1, and CD155 was 42.4%, 54.2%, and 52.1%, respectively. PD-1, TIM-3, and TIGIT axes may reduce T cell function in the CRC tumor microenvironment.

Tumor Mutational Burden Predicting the Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review and Meta-Analysis.

ObjectivesFor colorectal cancer patients, traditional biomarker deficient mismatch repair/microsatellite instability (dMMR/MSI) is an accurate predictor of immune checkpoint inhibitors (ICIs). Recent years, researchers considered tumor mutation burden (TMB) as another predictive biomarker which means the number of nonsynonymous mutations in cancer cells. Several studies have proven that TMB can evaluate the efficacy of ICI therapy in diverse types of cancer, especially in non-small cell lung cancer and melanoma. However, studies on the association between TMB and the response to ICI therapy in colorectal cancer alone are still lacking. In this study, we aim to verify the effect of TMB as a biomarker in predicting the efficacy of ICIs in colorectal cancer.MethodsWe searched the PubMed and Ovid MEDLINE databases up to May 1, 2021 and screened studies for eligibility. Thirteen studies published from 2015 to 2021 with 5062 patients were included finally. We extracted and calculated hazard ratios (HRs) and odds ratios (ORs) of overall survival (OS) and objective response rates (ORRs) and their 95% confidence intervals (95% CIs). Pooled HR and OR were evaluated to compare OS and ORR between TMB-high and TMB-low groups in colorectal cancer patients. Meanwhile, we assessed heterogeneity with the I 2 statistic and p-values and performed publication bias assessments, sensitivity analyses, and subgroup analyses to search the cause of heterogeneity.ResultsThe TMB-high patient group had a longer OS than the TMB-low patient group (HR = 0.68, 95% CI: 0.51, 0.92, p = 0.013) among colorectal cancer patients receiving ICIs. In addition, the TMB-high patient group was superior in terms of ORR (OR = 19.25, 95% CI: 10.06, 36.82, p < 0.001) compared to the TMB-low patient group.ConclusionsIn conclusion, this meta-analysis revealed that TMB can be used as a potential predictive biomarker of colorectal cancer patients receiving ICI therapy. Nevertheless, this finding is not stable enough. Therefore, many more randomized controlled trials are needed to prove that TMB is reliable enough to be used clinically to predict the efficacy of immunotherapy in colorectal cancer. And the most relevant biomarker remains to be determined when TMB high overlaps with other biomarkers like MSI and TILs.

Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects.

Immunotherapy is a new pillar of cancer therapy that provides novel opportunities to treat solid tumors. In this context, the development of new drugs targeting immune checkpoints is considered a promising approach in colorectal cancer (CRC) treatment because it can be induce specific and durable anti-cancer effects. Despite many advances in the immunotherapy of CRC, there are still limitations and obstacles to successful treatment. The immunosuppressive function of the tumor microenvironment (TME) is one of the causes of poor response to treatment in CRC patients. For this reason, checkpoint-blocking antibodies have shown promising outcomes in CRC patients by blocking inhibitory immune checkpoints and enhancing immune responses against tumors. This review summarizes recent advances in immune checkpoint inhibitors (ICIs), such as CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 in CRC, and it discusses various therapeutic strategies with ICIs, including the double blockade of ICIs, combination therapy of ICIs with other immunotherapies, and conventional treatments. This review also delineates a new hopeful path in the combination of anti-PD-1/anti-PD-L1 with other ICIs such as anti-CTLA-4, anti-LAG-3, and anti-TIM-3 for CRC treatment.

MiR-148a-3p silences the CANX/MHC-I pathway and impairs CD8+ T cell-mediated immune attack in colorectal cancer.

Nonresponse, or acquired resistance to immune checkpoint inhibitors in colorectal cancer (CRC) highlight the importance of finding potential tolerance mechanisms. Low expression of major histocompatibility complex, class I (MHC-I) on the cell surface of the tumor is one of the main mechanisms of tumor escape from T-cell recognition and destruction. In this study, we demonstrated that a high level of calnexin (CANX) in the tumors is positively correlated with the overall survival in colorectal cancer patients. CANX is a chaperone protein involved in the folding and assembly of MHC-I molecules. Using miRNA target prediction databases and luciferase assays, we identified miR-148a-3p as a potential regulator of CANX. Inhibition of miR-148a-3p restores surface levels of MHC-I and significantly enhanced the effects of CD8+ T-cell-mediated immune attack in vitro and in vivo by promoting CANX expression. These results reveal that miR-148a-3p can function as a tumor promotor in CRC by targeting the CANX/MHC-I axis, which provides a rationale for immunotherapy through targeting the miR-148a-3p/CANX/MHC-I pathway in patients with CRC.

Abstract 1681: Correlation of BRCA1/2 mutations with response to immune checkpoint inhibitors in colorectal cancer

Abstract Background: BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair. They have been found to promote both tumor initiation and progression. BRCA1/2 mutations lead to genomic instability and higher tumor mutation burden (TMB). Therefore, we hypothesized that BRCA1/2 mutations may be a predictor of immune checkpoint inhibitors (ICIs) efficacy. In the present work, we explored the correlation of BRCA1/2 mutations with TMB, high microsatellite instability (MSI-H), PD-L1 expression, tumor-infiltrating lymphocytes (TILs), and ICIs efficacy in colorectal cancer. Methods: A total of 509 Chinese colorectal cancer patients were enrolled from January 2017 to January 2020 in our center. Targeted next-generation sequencing and PD-L1 immunohistochemistry (22C3 antibody) were performed in the tissues from patients. TCGA colorectal cancer cohort was used for characterizing TILs with CIBERSORT. The ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of BRCA1/2 mutations with ICIs efficacy. Results: In our cohort, the mutational frequency of BRCA1/2 genes was 9.04%. The median TMB was significantly higher in the BRCA1/2 mutations (Mut) group compared to the wild type (WT) group (52.4 vs 5.7 muts/Mb, P &amp;lt; 0.0001). About 41.30% of patients have MSI-H in the Mut group, while 3.67% of patients display MSI-H in the WT group (P &amp;lt; 0.0001). There was no association of BRCA1/2 mutations with PD-L1 expression (P = 0.172). In TCGA cohort, BRCA1/2 mutations can down-regulate regulatory T (T reg) cells (P = 0.0176) and up-regulate T follicular helper cells (P = 0.0042) and macrophages M1 (P &amp;lt;0.0001). In MSKCC cohort, patients in the Mut group had significantly longer median overall survival after ICIs therapy (34 vs 13 months, HR: 0.37 [95%CI: 0.19-0.72], P = 0.0234). Conclusions: Our data indicated that BRCA1/2 mutations are associated with increased TMB and MSI-H, but not with PD-L1 expression. And BRCA1/2 mutations can regulate TILs. Furthermore, BRCA1/2 mutations are associated with better response to ICIs, suggesting that they may be a useful predictor for ICIs efficacy in colorectal cancer. Citation Format: Dong-Dong Jia, Yanling Niu, Tonghui Ma, Min Shi. Correlation of BRCA1/2 mutations with response to immune checkpoint inhibitors in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1681.

Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer.

Colorectal cancer (CRC) is the third commonest cancer globally, with metastasis being the reason for cancer-associated mortality. Much is still unknown biochemically about CRC, and with current treatments that are not wholly effective over time, new therapeutics are urgently needed. Emerging evidence has shown the importance of non-coding RNAs such as lncRNAs and miRNAs functions in the development and progression of CRC. However, the exact underlying mechanism of these types of RNAs in CRC is still mostly unknown. PI3K/AKT/mTOR pathway contributes to many cellular processes, and dysregulation of this pathway frequently occurs in cancers. In this review, the authors have mostly focused on the significant non-coding RNAs regulators of the PI3K/AKT/mTOR pathway and their contribution to the development or inhibition of CRC and their potential as diagnostic or therapeutic targets in CRC treatment.

RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways

Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.

Development of a protein signature to enable clinical positioning of IAP inhibitors in colorectal cancer

Resistance to chemotherapy-induced cell death is a major barrier to effective treatment of solid tumours such as colorectal cancer, CRC. Herein, we present a study aimed at developing a proteomics-based predictor of response to standard-of-care (SoC) chemotherapy in combination with antagonists of IAPs (inhibitors of apoptosis proteins), which have been implicated as mediators of drug resistance in CRC. We quantified the absolute expression of 19 key apoptotic proteins at baseline in a panel of 12 CRC cell lines representative of the genetic diversity seen in this disease to identify which proteins promote resistance or sensitivity to a model IAP antagonist [birinapant (Bir)] alone and in combination with SoC chemotherapy (5FU plus oxaliplatin). Quantitative western blotting demonstrated heterogeneous expression of IAP interactome proteins across the CRC cell line panel, and cell death analyses revealed a widely varied response to Bir/chemotherapy combinations. Baseline protein expression of cIAP1, caspase-8 and RIPK1 expression robustly correlated with response to Bir/chemotherapy combinations. Classifying cell lines into 'responsive', 'intermediate' and 'resistant' groups and using linear discriminant analysis (LDA) enabled the identification of a 12-protein signature that separated responders to Bir/chemotherapy combinations in the CRC cell line panel with 100% accuracy. Moreover, the LDA model was able to predict response accurately when cells were cocultured with Tumour necrosis factor-alpha to mimic a pro-inflammatory tumour microenvironment. Thus, our study provides the starting point for a proteomics-based companion diagnostic that predicts response to IAP antagonist/SoC chemotherapy combinations in CRC.

Defining and Targeting BRAF Mutations in Solid Tumors.

BRAF mutations are present in up to 8% of human cancers, and comprise a viable therapeutic target in many patients harboring these mutations. Specific BRAF-targeted therapies, such as vemurafenib, dabrafenib, and encorafenib, have transformed treatment of many BRAF-mutated cancers, producing meaningful clinical benefit with more tolerable safety profiles compared to prior standard-of-care treatments. BRAF inhibitors were first approved for use in metastatic melanoma, although resistance almost always limited their long-term effectiveness. Combination therapy with BRAF and MEK inhibitors has proven effective in delaying the onset of resistance, and produces additional clinical benefit across cancers. Although not promising initially in treatment of BRAF-mutated colorectal carcinoma, BRAF inhibitors in colorectal cancer were successfully combined with EGFR inhibitors, resulting in significant treatment response. Refining the use of BRAF and MEK inhibitors in less common tumor types (and for non-V600 mutations) and delaying the development of resistance remain pertinent future considerations in treating BRAF-mutated cancers. In this review, we will discuss the prevalence of BRAF mutations across human cancers and evidence on the efficacy and safety of current management strategies for various BRAF-mutant solid tumors.

Dual inhibition of TGF\u03b2 and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype

A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease.

Hedgehog Signaling in Colorectal Cancer: All in the Stroma?

Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.

Autophagy and Ubiquitination as Two Major Players in Colorectal Cancer: A Review on Recent Patents.

As one of the most commonly diagnosed cancers among men and women, Colorectal Cancer (CRC) leads to high rates of morbidity and mortality across the globe. Recent anti- CRC therapies are now targeting specific signaling pathways involved in colorectal carcinogenesis. Ubiquitin Proteasome System (UPS) and autophagy are two main protein quality control systems, which play major roles in the carcinogenesis of colorectal cancer. A balanced function of these two pathways is necessary for the regulation of cell proliferation and cell death. In this systematic review, we discuss the available evidence regarding the roles of autophagy and ubiquitination in progression and inhibition of CRC. The search terms "colorectal cancer" or "colon cancer" or "colorectal carcinoma" or "colon carcinoma" in combination with "ubiquitin proteasome" and "autophagy" were searched in PubMed, Web of Science, and Scopus databases, and also Google Patents (https://patents.google .com) from January 2000 to Feb 2020. The most important factors involved in UPS and autophagy have been investigated. There are many important factors involved in UPS and autophagy but this systematic review shows the studies that have mostly focused on the role of ATG, 20s proteasome and mTOR in CRC, and the more important factors such as ATG8, FIP200, and TIGAR factors that are effective in the regulation of autophagy in CRC cells have not been yet investigated. The most important factors involved in UPS and autophagy such as ATG, 20s proteasome and mTOR, ATG8, FIP200, and TIGAR can be considered in drug therapy for controlling or activating autophagy.

Gut microbiota-derived metabolites and colorectal cancer: New insights and updates

Abundant evidence from in-vitro as well as in-vivo studies supports the gut microbiota-derived metabolites as crucial executors of diet effect on the host physiology. As such, a number of microbiota-derived metabolites produced from diet have been connected to complex forms of human diseases such as colorectal cancer (CRC). Despite current unresolved questions concerning molecular mechanisms between metabolites, host signaling pathways, and CRC, some new progresses promise continued advancement of the field. Therefore, clarification of the molecular events underlying which metabolites may regulate proliferation of colonocytes will hopefully open up new avenues for seeking the possibilities affecting host health and exploitation of these capabilities for therapeutic purpose. In this Review, we will discuss recent insights into contributions of the gut microbiota-derived metabolites to CRC and argue that the cumulative effects of metabolites should be considered with the intention of better predict and prevent cancer progression. We will also discuss the signaling pathways induced by specific metabolites toward down-regulation and/or up-regulation of immune system that eventually trigger progression and/or inhibition of CRC.

EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079.

Cotargeting BET proteins overcomes resistance arising from PI3K/mTOR blockade-induced protumorigenic senescence in colorectal cancer.

Therapeutics targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal-regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence-associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra-terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC.

Age, sex, and specific gene mutations affect the effects of immune checkpoint inhibitors in colorectal cancer

The effect of age and sex on the predictive value of colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs) has been controversial, and the effect of specific gene mutations on the predictive value of CRC patients treated with ICIs remains to be explored. Our study analyzed the influence of the above factors on the overall survival (OS) of CRC patients receiving ICIs and explored the influencing mechanism of various predictive biomakers. We performed survival prognostic correlation analysis and bioinformatics analysis on the clinical CRC cohort receiving ICIs in from the Memorial Sloan Kettering Cancer Center (MSKCC) and the clinical and genetic data from The Cancer Genome Atlas (TCGA)-CRC dataset, including immunogenicity analysis, tumor immune microenvironment analysis, and gene set enrichment analysis and so on. We found that mutation count >11 mutation/Mb (tumor mutation burden, TMB-high) (HR = 0.22, 95 %CI: 0.09−0.53; P < 0.001), male (HR = 0.51, 95 %CI: 0.28−0.93; P = 0.029), RNF43-mutant (MT) (HR = 0.12, 95 %CI: 0.03−0.49; P = 0.003), CREBBP-MT (HR = 0.23, 95 %CI: 0.07−0.76; P = 0.016), NOTCH3-MT (HR = 0.17, 95 %CI: 0.04−0.74; P = 0018), PTCH1-MT (HR = 0.27, 95 %CI: 0.08−0.9; P = 0.033), CIC-MT (HR = 0.23, 95 %CI: 0.05−0.93; P = 0.040), DNMT1-MT (HR = 0.12, 95 %CI: 0.02−0.93; P = 0.043) and SPEN-MT (HR = 0.31, 95 %CI: 0.09−0.99; P < 0.049) are all related to longer OS, but age≤65 years (HR = 3.01, 95 %CI: 1.18–7.65; P = 0.021), APC-MT (HR = 2.51, 95 %CI: 1.12–5.63; P = 0.026) and TP53-MT (HR = 1.94, 95 %CI: 1.03–3.65; P = 0.041) are associated with shorter OS. The reason why positive predictive markers provide survival benefits to CRC may be related to higher immunogenicity such as TMB, highly expression of mRNA related to immune response, highly infiltrating immune-active cells such as CD8 + T cells, active immune-active pathways, and DNA damage repair pathways with an increased number of mutations.

A New Compound with Increased Antitumor Activity by Cotargeting MEK and Pim-1.

SummaryFeedback circuits are one of the major causes underlying tumor resistance. Thus, compounds that target one oncogenic pathway with simultaneously blocking its compensatory pathway will be of great value for cancer treatment. Here, we develop a new MEK inhibitor designated as KZ-02 that exhibits unexpectedly higher cytotoxicity than its starting compound AZD6244, a well-known MEK inhibitor, in colorectal cancer (CRC). Subsequent kinase selectivity study identified Pim-1 as an additional cellular target for KZ-02. Further studies showed that AZD6244 and Pim-1 1 (a Pim-1 inhibitor) have a synergistic effect on CRC suppression. Mechanistic study revealed that MEK inhibition by AZD6244 leads to increased Pim-1 expression, which could be a general mechanism behind the compromised cell-killing activity of MEK inhibitors. KZ-02, despite increasing Pim-1 mRNA expression, simultaneously promotes Pim-1 proteasomal degradation. Therefore, we uncover a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1.

Abstract PHB05: Mechanism-based computational models to study interplay between EGFR inhibitors and KRAS mutants

Abstract An early genotype-to-phenotype relationship in cancer personalized medicine was that KRAS mutations confer resistance to EGFR inhibitors in colorectal cancer. Confusingly, phase 3 clinical trials found that patients with the KRAS G13D mutation were an exception to this rule. That constitutively active KRAS mutants would cause resistance to EGFR inhibitors seemed intuitive, and it appeared inconsistent with known mechanisms of RAS biology for any constitutively active KRAS mutant to behave differently. We have developed a computational model that describes the biochemical mechanisms of RAS signal regulation. Simulations of this mass-action model reproduce known patterns of RAS pathway activation. The incorporation of the specific biochemical parameters for different KRAS mutants has allowed us to uncover novel, non-obvious insights into the response of KRAS G13D and KRAS G12C colorectal cancers to EGFR inhibition. For KRAS G13D, the model revealed EGFR inhibition leads to reduced wild-type HRAS and NRAS signaling in KRAS G13D cancers, but not KRAS G12D or KRAS G12V cancers. The model also revealed a critical dependence upon tumor suppressor NF1, and that the impaired binding of KRAS G13D to NF1 frees NF1 to act on wild-type RAS. Importantly, our computational predictions have been prospectively validated experimentally. Our computational model has also revealed that cotreatment of KRAS G12C colorectal cancer with EGFR and KRAS G12C inhibitors results in a depletion of the active forms of both wild-type and mutant RAS proteins, which we have also confirmed experimentally. For both KRAS G13D and KRAS G12C colorectal cancers, our work demonstrates how computational models can identify behaviors that logically follow from what is known, but which the complexity of the RAS signaling network has prevented from previously being uncovered despite extensive, empirical, experimental efforts. This abstract is also being presented as Poster B51. Citation Format: Edward C. Stites. Mechanism-based computational models to study interplay between EGFR inhibitors and KRAS mutants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHB05.