RAS mutation

P1, N=614, Recruiting, Revolution Medicines, Inc. | Trial completion date: Dec 2025 --> Jun 2026

We demonstrated the feasibility of obtaining actionable information within a clinically meaningful turnaround time using a robust NGS solution. For samples with sufficient tumour content and DNA for testing (>90% of samples), Find It had an approximately 99% success rate. Actionable information provided by the panel could impact clinical management for 66% of advanced-stage cancer patients.

The detection of BRAF fusions and their many partners was enabled by the Afirma XA exome-enriched RNASeq panel. Although BRAF fusions occurred in only 0.2% of thyroid nodules, they were GSC-Suspicious and lacked typical BRAF/RAS mutations. Interestingly, expression signatures associated with malignancy varied by fusion partner.

P1/2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.

The prognosis of papillary thyroid carcinoma (PTC) is highly dependent on gene mutations and pathologic features.The common gene mutations in PTC include BRAF V600E,RET/PTC rearrangement,and RAS mutations.These mutations have been suggested to be associated with an increased risk of recurrence,poorer efficacy of postoperative radioactive iodine therapy,and reduced survival.The pathologic subtypes of PTC include classic,follicular,tall cell,hobnail,columnar cell,diffuse sclerosing,solid/trabecular,oncocytic,Warthin-like,clear cell,and spindle cell subtypes,which have different aggressiveness and linked with varied clinical prognosis.Therefore,detecting the gene mutations and pathologic subtypes of PTC is of great importance for therapeutic regimen selection and prognosis evaluation.Ultrasound imaging with non-invasiveness,convenience,and high resolution has become the primary examination method for the diagnosis and treatment of thyroid cancer.This paper reviews the correlations of gene mutations and pathologic subtypes with the ultrasound features of PTC,aiming to give new insights into the application of ultrasound imaging in predicting gene mutations and pathologic subtypes of PTC before surgery as well as provide new ideas for accurate assessment of preoperative prognosis.

P1/2, N=83, Recruiting, Virginia Commonwealth University | Trial completion date: Dec 2025 --> May 2026 | Trial primary completion date: Dec 2024 --> May 2025

Moreover, USP7 inhibitors suppress NSCLC cell proliferation, particularly in cells resistant to the KRAS-G12C inhibitor AMG510. In conclusion, our findings identify USP7 as a key deubiquitinase regulating RAS stability, and targeting USP7 is a promising strategy to counteract KRAS inhibitor resistance in NSCLC.

This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.

P2, N=70, Active, not recruiting, Inspirna, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Aug 2028 --> Dec 2026 | Trial primary completion date: Aug 2026 --> Sep 2025

These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.

Results suggest that aflibercept plus FOLFIRI, after failure of a prior oxaliplatin-based regimen, allows R0/R1 resection of CLM in almost 20 % of patients with a major pathological response in most cases and a median OS prolonged by more than 3-fold versus non-resected patients.

We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.

RAS mutants most sensitive to stimulation of GTPase activity were more susceptible to treatment compared to mutants whose hydrolysis could not be enhanced, suggesting that pharmacologic stimulation of hydrolysis potentiates the therapeutic effects of tri-complex inhibitors for specific RAS mutants. This study lays the foundation for developing a new class of therapeutics that inhibit cancer growth by stimulating mutant GTPase activity.

Additionally, early detection of implantation and subsequent curative resection were common outcomes, suggesting the importance of vigilant surveillance. Further research and preventive measures such as thorough intraluminal lavage and complete closure of ulcers may be crucial in minimizing implantation risks post-endoscopic treatment.

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

This finding may also help explain the limited clinical responses to metformin in cancers with RAS mutations. Ultimately, our study underscores the importance of understanding the impact of the genetic landscape in tailoring precision cancer preventive approaches in the context of HNSCC and other cancers that are characterized by the presence of a defined premalignant state and, therefore, amenable for cancer interception strategies.

The patient underwent surgical treatment and had no neurological sequelae. By presenting such a clinical case, attention is paid to the interrelationship between genetic syndromes and intracranial tumors.

Consistent with existing literature, our findings showed no survival benefit from locoregional treatments such as surgery of the primary tumor or curative radiotherapy at diagnosis. In contrast, resection of hepatic metastases was associated with improved survival outcomes.

Although significant improvements in CRC management have occurred globally in recent years, a strategic approach leading to population-based systemic solutions is required. The high incidence of young-onset CRC and the growing elderly population due to a rise in life expectancy will be especially important factors for countries with limited healthcare resources like Serbia.

To our knowledge, this is the first report of prominent pervasive oncogenic role of RAS mutations revealed by gene dependency data that is beyond the current understanding of the oncogenic role of RAS genes and their well-known involved tissue types. Our findings strongly support RAS mutations as primary oncogenic drivers beyond traditionally recognized cancer types and offer insights into their tissue-specific permissiveness.

Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS. ClinicalTrials.gov Identifier: NCT03181100.

P1, N=131, Completed, BeiGene | Phase classification: P1a/1b --> P1

Given the profound increases observed in RPS6KA1/p90RSK phosphorylation, future work will involve a determination whether the proapoptotic isoforms of RPS6KA1/p90RSK are phosphorylated due to the PCAIs treatments. These results support the potential use of the PCAIs as targeted therapies against cancers with KRAS mutations.

Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.

ADC values above 1.339 x 10-3mm2/s with 87% sensitivity and 89% specificity indicate post-radiation proctitis in relation to normal wall. The ADC is a useful marker in differentiating between rectal cancer, post-radiation proctitis, and normal rectal wall with high sensitivity and specificity, but it cannot be used to distinguish the histological grades of rectal cancer, nor other pathohistological parameters.

ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

For nodules classified as Bethesda Ⅲ-Ⅴ, the sensitivity and specificity were 63.0% and 100.0%, respectively, with an AUC (95%CI) of 0.815 (0.680-0.950). NGS technology can successfully detect multiple gene mutations in US-FNA specimens from TMN patients, especially BRAF gene mutation, and BRAF gene mutation has certain value in diagnosing TMC.

P1, N=53, Terminated, Pfizer | Trial completion date: Nov 2025 --> Jun 2024 | Active, not recruiting --> Terminated; The study was prematurely discontinued due to strategic reasons, not major safety concerns, futility, or requests from any regulatory authorities

The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supporting by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.

The number of patients with prior regorafenib treatment was 14 in the TAS-102 with bevacizumab group and 5 in the TAS-102 alone group. The combination of TAS-102 and bevacizumab resulted in a better survival outcome than TAS-102 monotherapy, consistent with previous studies. This analysis supports the use of the combination of TAS-102 and bevacizumab as the best therapeutic option for patients with refractory metastatic colorectal cancer in clinical practice.

ThyraMIRv2 platform does not improve indeterminate thyroid nodule malignancy stratification compared to ThyGeNEXT-ThyraMIRv1 multiplatform test version 1. ThyraMIRv2 improves malignant RAS-mutated nodule detection but increases false positives. Future studies encompassing a larger cohort of RAS-mutated with surgical pathology results are warranted to better characterize the performance parameters of this classifier.

Actionable gene fusions are more prevalent in MSI-H, RAS/BRAF wildtype, or RNF43-mutated CRC, as well as in colon cancer. Mapping of these molecular markers can markedly increase the fusion detection rate, which can help clinicians select candidates for fusion testing and targeted therapy.

While the effectiveness of MEK inhibitors such as selumetinib is established in NF1-associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS-driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling.

The finding of synchronous mutations is a rare occurrence suggesting for intratumoral heterogeneity (ITH) even in PTC. Patients with multiple mutations have a clinical worse prognosis, generally characterized by an aggressive thyroid cancer, which may influence the surgical treatment, chemotherapy, and BRAF V600E mutation-targeting therapy.

Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation.

KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high-risk.

Here, we discuss the favouring of kinase pathways across an array of Ras-mutant oncogenic contexts and assess recent advances in pharmacological targeting of various Ras mutants. Ultimately, we will examine the utility of individualised pharmacological approaches to Ras-mediated cancer.

P3, N=460, Recruiting, Revolution Medicines, Inc.

miRNA pairwise expression profiling enhances the miRNA algorithmic classifier and mutation status in assessing malignancy risk and allowed for further stratification of both RAS-positive and mutation-negative Bethesda V thyroid nodules.

While recurrence data were not available for this series of radiation-induced PTCs, Type 3 and advanced Type 1/2 cancers defined by Thyroid GuidePx® had more aggressive clinical features, including a higher rate of RET fusions, a surrogate marker for recurrence risk in radiation-induced PTC.

Biospecimens from patients with stage I/II LUAD show TNC in regions of FAK activation and an association of TNC with tumor recurrence after primary tumor resection. These results suggest that exogenous insults that elevate TNC in the lung parenchyma interact with tumor-initiating mutations to drive early LUAD progression and local recurrence.