Potential benefit of treatment with MEK inhibitors and chemotherapy in BRAF-mutated KRAS wild-type pancreatic ductal adenocarcinoma patients: a case report.
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ABSTRACT:
SUBMITTER: Ardalan B
PROVIDER: S-EPMC8559623 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.
| S-EPMC7594413 | biostudies-literature
Project description:ObjectivesSurvival benefit of combination over single-agent chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) was demonstrated in younger patients in clinical trials. The authors aimed to evaluate whether this survival benefit of combination chemotherapy is present in elderly patients with metastatic PDAC.Materials and methodsThe authors identified elderly patients (age 65 y or older) with stage IV PDAC and extracted available clinical information from a prospectively maintained institutional pancreatic cancer registry from 2007 to 2016. The primary endpoint was overall survival. Cox proportional hazards regression was used for multivariable survival analyses. Survival outcomes for the entire cohort and by age group I (elderly, 65 to 75 y) and age group II (very elderly, older than 75 y) were assessed.ResultsA total of 606 patients were included with a median age of 73.8 years. Among them, 239 patients (39%) received combination chemotherapy and 152 patients (25.1%) received single-agent chemotherapy as first-line treatment. Combination chemotherapy was associated with significantly longer median overall survival compared with single-agent chemotherapy (10.9 vs. 7.5 mo, P<0.001) with hazard ratio 0.62 (95% confidence interval, 0.47-0.81; P=0.001) after adjusting for age, sex, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, and carbohydrate antigen 19-9 level. Analyses by age groups indicated that very elderly patients (age group II) benefited from combination chemotherapy compared with single-agent chemotherapy with hazard ratio 0.56 (95% confidence interval, 0.31-1; P=0.049), comparable with the age group I (Page-treatment interaction=0.81).ConclusionElderly patients, even those older than 75 years, with metastatic PDAC benefited from combination chemotherapy.
| S-EPMC7395872 | biostudies-literature
Project description:Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations.
| S-EPMC9497071 | biostudies-literature
Project description:Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptosis. NCK also abrogated the growth of preformed colonies of PDAC cells in 3D culture. Furthermore, high-throughput screening with an oncology drug library to identify potential combinations revealed a strong synergistic effect between NCK and MEK inhibitors in PDAC cells harboring either wild-type or mutant-KRAS. Mechanistically, both mutant-KRAS and MEK inhibition increased the phosphorylation of BADS99 in PDAC cells, an effect abrogated by NCK. Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.
| S-EPMC10897366 | biostudies-literature
Project description:Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC. Several selective inhibitors of MEK have entered clinical trial evaluation; however, clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable. Amplification of the driving oncogene KRAS(13D), which increases signaling through the ERK1/2 pathway, upregulation of the noncanonical wingless/calcium signaling pathway (Wnt), and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC. The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations. Thus, dual targeted inhibition of MEK and PI3K pathway effectors (mTOR, PI3K, AKT, IGF-1R or PI3K/mTOR inhibitors) presents a potential strategy to overcome resistance to MEK inhibitor therapy. Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors.
| S-EPMC4613347 | biostudies-literature
Project description:Purpose: Adjuvant chemotherapy following resection is recommended by clinical practice guidelines for all patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the efficacy of adjuvant chemotherapy among the staging groups of the American Joint Committee on Cancer (AJCC) for PDAC. Patients and Methods: This retrospective cohort analysis was performed by the Surveillance Epidemiology and End Results (SEER) (2004-2015) database and multi-institutional dataset (2010-2018). Baseline clinicopathologic characteristics of PDAC patients, including age, gender, ethnicity, marital status, education level, county income level, county unemployed rate, insurance status, grade, stage, chemotherapy, and radiotherapy, were collected. Overall survival (OS) was analyzed using the Kaplan-Meier method. The SEER and multi-institutional data were adjusted with 1:1 ratio propensity score matching (PSM). Results: In total, 6,274 and 1,361 PDAC patients were included from the SEER database and multi-institutional dataset, respectively. Regardless of the count of resected lymph nodes, adjuvant chemotherapy prolonged the long-term OS time for stage IB, IIA, IIB, and III patients in both SEER and multi-institutional cohorts. Nevertheless, adjuvant chemotherapy did not provide additional clinical benefits even after a PSM adjustment for stage IA patients in both SEER and multi-institutional cohorts. Conclusion: Adjuvant chemotherapy improved the long-term survival of stage IB, IIA, IIB, and III PDAC patients; however, it demonstrated no survival benefit in stage IA PDAC patients. Thus, adjuvant chemotherapy should not be recommended for stage IA PDAC patients. These would significantly reduce the economic burden of society and improve the life quality of stage IA PDAC patients.
| S-EPMC7379031 | biostudies-literature
Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among all solid tumors. Tumorigenesis is promoted by the oncogene KRAS, and KRAS mutations are prevalent in patients with PDAC. Therefore, a comprehensive understanding of the interactions between KRAS mutations and PDAC may expediate the development of therapeutic strategies for reversing the progression of malignant tumors. Our study aims at establishing and validating a prediction model of KRAS mutations in patients with PDAC based on survival analysis and mRNA expression.MethodsA total of 184 and 412 patients with PDAC from The Cancer Genome Atlas (TCGA) database and the International Cancer Genome Consortium (ICGC), respectively, were included in the study.ResultsAfter tumor mutation profile and copy number variation (CNV) analyses, we established and validated a prediction model of KRAS mutations, based on survival analysis and mRNA expression, that contained seven genes: CSTF2, FAF2, KIF20B, AKR1A1, APOM, KRT6C, and CD70. We confirmed that the model has a good predictive ability for the prognosis of overall survival (OS) in patients with KRAS-mutated PDAC. Then, we analyzed differential biological pathways, especially the ferroptosis pathway, through principal component analysis, pathway enrichment analysis, Gene Ontology (GO) enrichment analysis, and gene set enrichment analysis (GSEA), with which patients were classified into low- or high-risk groups. Pathway enrichment results revealed enrichment in the cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450, and viral protein interaction with cytokine and cytokine receptor pathways. Most of the enriched pathways are metabolic pathways predominantly enriched by downregulated genes, suggesting numerous downregulated metabolic pathways in the high-risk group. Subsequent tumor immune infiltration analysis indicated that neutrophil infiltration, resting CD4 memory T cells, and resting natural killer (NK) cells correlated with the risk score. After verifying that the seven gene expression levels in different KRAS-mutated pancreatic cancer cell lines were similar to that in the model, we screened potential drugs related to the risk score.DiscussionThis study established, analyzed, and validated a model for predicting the prognosis of PDAC based on risk stratification according to KRAS mutations, and identified differential pathways and highly effective drugs.
| S-EPMC10805828 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a poor overall prognosis. However, curative resection during the early stages of the disease can greatly improve survival rates, highlighting the importance of early screening and detection. Studies of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), provide important insights into strategies for the early detection of KRAS-driven PDAC. Here, we summarize our studies and review current reports on research investigating KRAS-related miRNAs and lncRNAs, emphasizing their aberrant expression, mechanisms, carcinogenic effects, and prognostic and predictive capacities in PDAC.
| S-EPMC5643763 | biostudies-literature
Project description:BackgroundData supporting the routine use of adjuvant chemotherapy (AC) compared with no AC (noAC) following neoadjuvant chemotherapy (NAC) and resection for pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to determine whether AC improves long-term survival in patients receiving NAC and resection.MethodsPatients receiving resection for PDAC following NAC from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). Patients with a survival rate of < 6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression analysis were performed to account for selection bias and analyze the impact of AC on overall survival.ResultsOf 4449 (68%) noAC patients and 2111 (32%) AC patients, 2016 noAC patients and 2016 AC patients remained after PSM. After matching, AC was associated with improved survival (median 29.4 vs. 24.9 months; p < 0.001), which remained after multivariable adjustment (HR 0.81, 95% confidence interval [CI] 0.75-0.88; p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (hazard ratio [HR] 0.80, 95% CI 0.72-0.90; p < 0.001), N1 (HR 0.76, 95% CI 0.67-0.86; p < 0.001), R0 margin status (HR 0.82, 95% CI 0.75-0.89; p < 0.001), R1 margin status (HR 0.77, 95% CI 0.64-0.93; p = 0.007), no neoadjuvant radiotherapy (NART; HR 0.84, 95% CI 0.74-0.96; p = 0.009), and use of NART (HR 0.80, 95% CI 0.73-0.88; p < 0.001). Stratified analysis by nodal, margin, and NART status demonstrated consistent results.ConclusionAC following NAC and resection is associated with improved survival, even in margin-negative and node-negative disease. These findings suggest completing planned systemic treatment should be considered in all resected PDACs previously treated with NAC.
| S-EPMC8460503 | biostudies-literature
Project description:PurposeThe benefit of adjuvant chemotherapy following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant FOLFIRINOX is unclear. This study aimed to assess the survival benefit of adjuvant chemotherapy in this patient population.Materials and methodsThis retrospective study included 218 patients with localized non-metastatic PDAC who received neoadjuvant FOLFIRINOX and underwent curative-intent surgery (R0 or R1) between January 2017 and December 2020. The association of adjuvant chemotherapy with disease-free survival (DFS) and overall survival (OS) was evaluated in overall patients and in the propensity score matched (PSM) cohort. Subgroup analysis was conducted according to the pathology-proven lymph node status.ResultsAdjuvant chemotherapy was administered to 149 patients (68.3%). In the overall cohort, the adjuvant chemotherapy group had significantly improved DFS and OS compared to the observation group (DFS: median, 13.8 months [95% confidence interval (CI), 11.0 to 19.1] vs. 8.2 months [95% CI, 6.5 to 12.0]; p < 0.001; and OS: median, 38.0 months [95% CI, 32.2 to not assessable] vs. 25.7 months [95% CI, 18.3 to not assessable]; p=0.005). In the PSM cohort of 57 matched pairs of patients, DFS and OS were better in the adjuvant chemotherapy group than in the observation group (p < 0.001 and p=0.038, respectively). In the multivariate analysis, adjuvant chemotherapy was a significant favorable prognostic factor (vs. observation; DFS: hazard ratio [HR], 0.51 [95% CI, 0.36 to 0.71; p < 0.001]; OS: HR, 0.45 [95% CI, 0.29 to 0.71; p < 0.001]).ConclusionAmong PDAC patients who underwent surgery following neoadjuvant FOLFIRINOX, adjuvant chemotherapy may be associated with improved survival. Randomized studies should be conducted to validate this finding.
| S-EPMC10372602 | biostudies-literature