RAS wild-type

P2, N=50, Active, not recruiting, Rutgers, The State University of New Jersey | Trial completion date: Mar 2024 --> Mar 2026

Therefore, in the presence of MSI-H/MMRd and an additional actionable target, we prefer treating with targeted therapy and reserving immunotherapy for later lines. Pt preference has to be taken into consideration at all times though.

TRIPLETE is a phase III trial where 435 pts with RAS/BRAF wt – per local assessment – mCRC were randomized to receive first-line FOLFOX/ panitumumab (pan) or mFOLFOXIRI/pan... In contrast to previous data, negative hyperselection both through tissue and plasma analysis failed to demonstrate a prognostic role among pMMR RAS/BRAF wt mCRC pts treated with first-line chemotherapy plus pan. The confounding effect of the associated chemotherapy is a potential explanation for this finding. Tissue and plasma analyses at baseline failed to provide fully concordant results.

The LIBImAb Study is a phase III, randomized, openlabel, comparative, multi-center trial to assess the superiority in terms of efficacy of bevacizumab versus cetuximab in combination with FOLFIRI in mCRC pts, RAS/BRAFwt on tumor tissue and RAS/BRAF mutant (RAS/BRAFmut) at liquid biopsy... These data indicate the feasibility of cfDNA-based prospective enrolment in an interventional trial using a test with a rapid TAT for screening of RAS/ BRAF status in plasma. Our preliminary findings also suggest that ctDNA testing might better recapitulate the tumor heterogeneity of mCRC pts thus complementing tissue genomic profiling.

Among 22 HER2-positive/heterogenous cases with successful ISH testing, 100% (22/22) demonstrated amplification via ISH. Because the classification of tumors as HER2-positive/heterogenous by IHC correlated very closely with ISH positivity, our results suggest that ISH is likely unnecessary for CRCs with 3+ HER2 overexpression in 10-49% of neoplastic cells.

This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.

P4, N=110, Active, not recruiting, Rennes University Hospital | Trial primary completion date: Sep 2024 --> Jun 2025

Mechanistically, TMOD3 promoted F-actin polymerization, thereby facilitating the fusion of autophagosomes with lysosomes, increasing the degradation of the ACSL4 protein, and augmenting the ferroptosis-inducing effects of RSL3...Cangrelor, an FDA-approved drug, can target TMOD3...In conclusion, TMOD3 was found to inhibit ferroptosis and induced the resistance to PD-1 antibody by facilitating the fusion of autophagosomes and lysosomes through the promotion of F-actin polymerization in KRAS-mutant PC. TMOD3 was identified as a novel target for PC therapy.

P1/2, N=18, Active, not recruiting, Cantex Pharmaceuticals | Recruiting --> Active, not recruiting

P2, N=58, Not yet recruiting, Xuancheng People's Hospital; Xuancheng People's Hospital of Anhui Province

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.

P2, N=122, Completed, Daiichi Sankyo | Active, not recruiting --> Completed | Trial completion date: Jul 2024 --> Oct 2024

The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.

These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain, independent of other cooperating signals. .

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.

P3, N=480, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Further, G48C, Q43K, and E37K all have less negative ΔG values, indicating a weaker GDP-binding affinity compared to wild-type NRAS. Taken together, the results suggest that oncogenic readouts of NRAS mutants are codon- and mutation-specific, with potential repercussions on the aggressiveness, resistance, and therapeutic response.

P1, N=64, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.

Non-low grade of tumor budding, and high SII level were independently associated with KRAS mutation in CRC. It provides additional references for diagnosis and treatment options for patients with CRC.

P1/2, N=81, Recruiting, Cancer Research UK | N=135 --> 81

These methods have been applied as a proof-of-concept to KRAS and have shown they can predict known cryptic binding sites. Furthermore, we performed ligand-binding simulations of a known inhibitor (MRTX1133) to shed light on the nature of cryptic pockets in KRASG12D and the role of conformational selection vs induced-fit mechanism in the formation of these cryptic pockets.

We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.

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.

Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.

P2, N=2, Terminated, Shanghai Henlius Biotech | N=49 --> 2 | Trial completion date: Apr 2026 --> Dec 2023 | Suspended --> Terminated | Trial primary completion date: Aug 2024 --> Dec 2023; Due to poor clinical trial accrual, the study was terminated.

P1/2, N=125, Recruiting, Kahr Medical | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

We used the combined chemotherapy of gemcitabine (1,000 mg/m2) + oxaliplatin (135 mg/m2) + nimotuzumab (400 mg). Then, the patients were treated with oral olaparide (600 mg/day) for one year, and survived without tumor progress for more than 1.5 years. These two cases achieved excellent effects of precise chemotherapy, which provided an important reference for the treatment of pancreatic cancer patients with wild KRAS and mutant BRCA.

The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model.

After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

Pathway enrichment analyses using GO and KEGG, along with protein-protein interaction network and single sample gene set enrichment analyses, revealed key pathways and immune cell associations linked to ARHGEF5. These findings suggest that ARHGEF5 overexpression could serve as a biomarker for unfavorable outcomes in AML, providing insights into the underlying mechanisms of AML onset and progression.

P2, N=0, Withdrawn, Roswell Park Cancer Institute | N=20 --> 0 | Not yet recruiting --> Withdrawn

P1, N=129, Completed, Hutchison Medipharma Limited | Active, not recruiting --> Completed

P2, N=40, Recruiting, The University of Texas Health Science Center at San Antonio | Trial completion date: Feb 2025 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Feb 2026

No abstract available

P1, N=64, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P3, N=66, Active, not recruiting, Institut du Cancer de Montpellier - Val d'Aurelle | Recruiting --> Active, not recruiting

P1/2, N=22, Active, not recruiting, Laekna Limited | Recruiting --> Active, not recruiting | N=167 --> 22

P2, N=13, Not yet recruiting, Nanfang Hospital of Southern Medical University; Nanfang Hospital of Southern Medical University

P1/2, N=68, Not yet recruiting, Cancer Hospital Chinese Academy of Medical Sciences; Cancer Hospital Chinese Academy of Medical Sciences

P1/2, N=52, Completed, TyrNovo Ltd. | Active, not recruiting --> Completed | N=110 --> 52

CRLM with RAS mutations should be considered for strict surgical indications with preoperative chemotherapy and thorough examination, considering the possibility of short SCP.