EGFR mutation + KRAS mutation

The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA)...Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.

Due to the complexity of genetic divergence, inputs from each individual ancestry seem to carry independent contributions that interplay in the development of these complex disease phenotypes. By understanding these unique population characteristics, genomic ancestries hold a promising avenue for tailoring prognostic assessments and optimizing responses to oncological interventions.

RBC-bound tumor DNA is detectable in patients with early-stage Non-Small Cell Lung Cancer (NSCLC) but not in healthy controls by qPCR. Our results collectively uncover a previously unrecognized yet easily accessible reservoir of tumor DNA, offering a promising foundation for future RBC-based tumor diagnostics.

P3, N=1093, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Jun 2024

The circulating serum miR-133b and miR-206 can serve as significant biomarkers for monitoring the clinical outcome of progression with metastatic CRC patients. Increased drug-responsive CRC patients associated with crucial molecular intervention should be further explored, clinically.

The overall survival rate was significantly worse in lung adenocarcinomas with a cribriform pattern than in those without (hazard ratio 2.051, 95% CI 1.369-3.075). In conclusion, the presence of a cribriform pattern can be a useful predictor of the clinicopathological characteristics and prognosis of patients with lung adenocarcinoma.

Non-small cell lung carcinoma harboring FGFR3::TACC3 gene rearrangements is extremely rare, and this rearrangement may potentially be enriched in tumors that demonstrate clear cell histology. Identification of FGFR3::TACC3 in patients with lung carcinomas with clear cell features may be of importance as they could potentially be candidates for therapy with tyrosine kinase inhibitors.

Further investigation of biomarkers may allow patient selection for those who could benefit from anti-EGFR mAbs in combination with EGFR-TKIs. This review summarizes findings of recent studies of anti-EGFR mAbs in combination with EGFR-TKIs for the treatment of patients with EGFR-mutated NSCLC, as well as clinical evidence for potential biomarkers towards personalized targeted medicine.

Next generation sequencing using a 33 gene custom AmpliSeq panel was achieved in up to 72% of cases. In conclusion, small cytology and histology specimens obtained with ROSE are suitable for predictive biomarker testing in NSCLC, although attention needs to be paid to obtaining sufficient cells (>100) for PD-L1 immunohistochemistry.

Knockdown of p62 rescued the cells from Cu E-mediated anti-proliferative effect, apoptosis, DNA damage, and ROS production. These findings suggest that Cu E is a promising drug candidate for NSCLC.

Our study demonstrates the potential of radiomics in the non-invasive identification of EGFR and KRAS mutation status, which may guide patients with non-small cell lung cancer to choose the most appropriate personalized treatment. This method can be used when biopsy will bring unacceptable risk to patients with NSCLC.

Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.

In a real-world cohort of patients with NSCLC, we identified race-associated differences in therapeutic outcomes and described molecular characteristics in NHB and NHW patients with NSCLC. To proactively identify patients most likely to respond to systemic therapies, a more comprehensive approach is needed to help guide therapy selection in individualized patient populations.

The Multi-layer Perceptron model emerged as the top-performing model for both oncogenes, in some cases outperforming the state of the art. This study showed that radiomic features can be associated with EGFR and KRAS mutational status in patients with lung adenocarcinoma.

MET fusions are a rare, but potentially actionable, genomic alteration. Our study provides a comprehensive characterization of MET fusions in NSCLC, revealing their diverse fusion partners and co-occurring genomic alterations. Further research is warranted to elucidate the clinical implications of MET fusions in the treatment of various types of cancer, including lung cancer.

Patients with KRAS mutations have worse prognosis than those with EGFR. Secondary nodules progress faster with a KRAS driver. Patients with KRAS multifocal disease should expect a high rate of eventual need for secondary nodule treatment.

Conclusion ROS1 IHC assessment in lung cancer as a screening tool is helpful to suspect molecular alterations in positive cases, revealing ROS1 rearrangement and/or other oncogenic driver mutations.Evaluation with the FISH technique should be performed.In discordant cases with no molecular correlation of ROS1, ALK, KRAS, or EGFR; NGS or RT-PCR for ROS1 can be run to exclude rare mutations or undetected fusion partners with FISH. ROS-1 rearrangement can have co-mutations with EGFR, KRAS, and ALK setting a challenge for medical treatment.

Spatial analyses indicated statistically significant differences in the organization of these cell types between the 3 groups. ConclusionThe results of our study show that ultra-high plex immunofluorescence on TMA slides combined with adequate computational tools provides a unique opportunity to better understand the spatiotemporal architecture of lung cancer and identify new therapeutic targets.

Our results demonstrated that the TCR repertoire was clearly associated with cancer mutational profile. The mechanism of how mutations affect the immune system and shape the TCR repertoire is yet to be investigated. >

A prognostic impact for NSCLC patients receiving adjuvant chemotherapy was not associated with PD-L1 expression, or with EGFR and KRAS mutations.

P3, N=1093, Active, not recruiting, Eli Lilly and Company | Trial completion date: Jul 2023 --> Dec 2023

Positive EGFR and KRAS mutation statuses were risk factors for recurrence in resected IASLC grade 2 and 3 patients. KRAS mutations were more likely to be confirmed in cases with an increased risk of recurrence. EGFR and KRAS mutation statuses should be evaluated simultaneously when assessing the risk of recurrence.

The combinations of erlotinib and osimertinib with selinexor in EGFR-mutant NSCLC cell lines (PC9 and H1975), and trametinib plus selinexor in KRAS-mutant NSCLC cell lines (A549, H460) were highly synergistic abolishing tumor cell proliferation. The predictive value of HMGB1 mRNA was confirmed in metastatic NSCLC pretreatment samples treated with ICI. Overall, the pattern of reduced tumor growth induced by triple combination therapy (ICI, trametinib and/or selinexor) in the Lewis lung carcinoma model warrants further assessment in a clinical trial.

Considering the limitations of data from a single institution, we observed a high prevalence of mutation in EGFR and KRAS, comparing with current literature. An association of positive PD-L1 among those with positive mutation in KRAS was identified in our sample. Concurrent mutations may represent distinct subsets in lung cancer patients and further investigation is needed to elucidate their prevalence and future role in guiding treatment of this group of patients.

FGFR3 :: TACC3 fusions may occur de-novo or as a secondary treatment resistance mechanism in NSCLC. These fusions appear to be enriched in smokers or former smokers and more frequently occur with squamous cell carcinoma histology and may demonstrate clear cell morphology by light microscopy. Identification of FGFR alterations is of particular importance given the lack of targeted therapeutic options for patients with squamous cell carcinoma.

Nearly half of the BRAF-V600E negative thyroid carcinoma samples harbored either KRAS or EGFR mutations. This finding suggests that in BRAF-V600E negative thyroid carcinoma samples, testing for RAS and EGFR mutation may be warranted for further therapeutic consideration.

14 (9.8%) samples were either unsuitable for processing, or failed DNA-NGS analysis. The mean processing time (from date of sample receipt in the molecular diagnostics laboratory to date of report) was 6.1 working days.View this table:View inline P100 Table 1 Clinical and demographic background of 143 specimens included in analysisConclusion EBUS-TBNA is a reliable method of tissue acquisition for DNA based NGS assay processing.

Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.

In-vivo experiments, using CCL20 blocking antibodies, show promising therapeutic opportunities, although current scientific literature is conflicting and a thorough investigation is warranted. In EGFR-mutated lung cancer, additional research is needed to assist therapy decisions.

IHC and mIF staining showed that KRAS-mutant GGO nodules displayed higher infiltration of CD4+ T cell and CD8+ T cell as well as stronger proliferation and immune inhibitory signals. Our study demonstrates a driver landscape of radiologically detectable GGO-associated pulmonary nodules in Chinese patients and supports that different driver patterns in RTK/RAS pathway are corresponding to different radiologic features.

Within this group, the prevalence of targetable oncogenic drivers within the IS phenotype, such as KRAS G12C, may represent the potential for novel ICI combination therapies. 4 These findings further highlight the importance of adding TME analysis to comprehensive biomarker testing in NSCLC

We identified a role for EGFR pathway activation in the expression of mACE2 in NSCLC cells, associated with increased sACE2 levels in patients. Therefore, it is of great interest to study SARS-CoV-2-infected EGFR-mutated NSCLC patients in greater depth in order to obtain a better understanding of how mACE2, sACE2, and SOC TKIs can affect the course of COVID-19.

All the uncommon mutants displayed higher sensitivity than both the wild type and BRAF-V600E towards PLX 8394 and LSN3074753...Notably, molecular dynamic (MD) simulation revealed that increased number of interactions caused enhanced sensitivity of G469R and N581S towards sorafenib. RAF kinase inhibitors were further classified into two groups as per their selectivity (Group I: BRAF-V600E-selective and Group II: CRAF-selective) based on which potential mutation-wise combinations of RAF kinase inhibitors were proposed to overcome resistance. Based on computational inhibitor sensitivity profiles, appropriate treatment strategies may be devised to prevent or overcome secondary drug resistance in lung cancer patients with uncommon mutations.

Furthermore, a pH-responsive nanocarrier (Hyaluronic acid - fused quinazolinone 6 nanoparticles) was designed and assessed using a dialysis bag approach under both normal and acidic circumstances that confirmed the pH-sensitive nature of NPs. Delightfully, the nanoparticles demonstrated selective cell viability reduction potential towards the lung cancer cell lines (A549 lung cancer cell lines) and were found to be largely devoid of cell growth inhibitory effects under normal settings (L929, mouse fibroblast cells).

Based on histopathological features and clinical course FLAC has been categorized into low-grade (L-FLAC) and high-grade (H-FLAC) subtypes. L-FLAC shows low nuclear atypia, prominent morule formation and has a pure pattern. H-FLAC typi-cally presents ≥50% foetal morphology and is often associated with other conventional types of lung adenocarcinoma.

Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.

STING is ubiquitously expressed in NSCLC and associated with T cell function genes, AC histology, EGFR, and KRAS mutations and improved overall survival.

The association of allele frequency of clinically relevant short variants in circulating-free DNA (cfDNA) and the association with overall survival (OS) for patients using real-world data was also assessed. The results of the association analysis indicated that VAF of the predictive biomarker mutation negatively correlated with OS of NSCLC patients.