BI-2865 / Boehringer Ingelheim - LARVOL DELTA

Pharmacological Inhibitors of Mutant Ras: Preclinical Studies, Biomarkers of Response and Rational Design of Combination Regimens. (IMS 2026) - "We thus evaluated the efficacy of inhibitors targeting specific KRAS mutants (e.g., G12C [MRTX-1257]; G12D [MRTX-1133]), a broader spectrum of KRAS mutants (BI-2865), or multiple mutant and wild-type RAS forms (e.g., RMC-6236 and RMC-7977) in preclinical models of MM...Finally, using in vitro pharmacological screening, we identified sensitizers and confirmed in vivo (NSG mice) that RMC-6236 combined with lenalidomide is more active than either agent alone. These findings map the complex molecular landscape underlying Ras inhibitor responses and can inform personalized clinical development of these agents in MM. ( authors with equal contribution)"

Preclinical • Solid Tumor • FGFR3 • IL6 • KRAS • NRAS • PPIA

Single-cell multiomic drug response profiling of PRISM-multiplexed cancer cell lines sequenced with SBX (AACR 2026) - "We treated the PRISM pool with two RAS inhibitors (BI-2865 and RMC-6236), as well as a negative control (DMSO) and a positive control (Panobinostat), and collected cells at early time points (3h and 12h) to capture initial drug response dynamics. Importantly, these protein changes frequently lacked a corresponding significant change in the expression of their encoding RNA transcripts, underscoring the power of multi-modal profiling to more comprehensively illuminate functional mechanisms driving drug response.Our study establishes a scalable paradigm for linking genotype, transcriptome, and proteome to pharmacologic phenotype at single-cell resolution across genetically diverse human models. These data, enabled with massively high-throughput sequencing using SBX, provide a rich resource for mechanistic discovery and rational design of combination therapies targeting the RAS pathway."

Preclinical • Oncology

ADT-007: A mechanistically distinct Pan-RAS inhibitor with capacity to escape acquired resistance common to other RAS inhibitors (AACR 2026) - "Furthermore, RAS mutant colon and pancreatic cancer cells did not develop resistance to ADT-007 under chronic exposure, in contrast to sotorasib, BI-2865, and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor they were exposed to. Moreover, the resistant cell lines exhibited cross-resistance to mechanistically distinct classes of RAS inhibitors, including pan-KRAS, pan-RAS, and allele-specific KRAS inhibitors, but not to ADT-007 or a second-generation inhibitor, ADT-030...Consistent with resistance experiments, ADT-1004 displayed superior efficacy than sotorasib or adagrasib in a xenograft model using a resistant MIA-PaCa-2. These findings support further development of ADT-1004 that holds promise for broad and durable efficacy against RAS-driven cancers."

Preclinical • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Preclinical evaluation of RAS pathway inhibitors in gastroesophageal adenocarcinoma (AACR 2025) - "Western blot analysis revealed differences in MAPK signaling amplitude between KRASAMP and KRASMUT cell lines after synchronization...The pan-KRAS (OFF) Inhibitor, BI-2865 inhibits KRAS altered GEA cell viability with an IC50 ranging from 0.2 - 1.4 μM in KRASAMP and KRASG12D mutant cell lines...The allosteric SHP2 inhibitor RMC-4550 demonstrated an IC50 of 0.08-6.67 μM in KRASAMP and KRASG12D lines...There was no adaptive signaling through PI3K pathways based on suppressed p-AKT levels, in comparison to trametinib which resulted in increases in pAKT. The RAF/MEK clamp VS-6766 also inhibits signaling through MAPK as evidenced by decreased p-AKT, and an EC50 for p-ERK of 131.83 nM (KRASAMP) and 10.4725 nM (KRASMUT) GEA cells...Our results suggest that combination strategies will be essential to overcome adaptive resistance and maximize therapeutic benefit in KRASAMP cells. Future in vivo studies will validate the potential of these inhibitors and combination approaches."

Preclinical • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • KRAS

Profiling Ras inhibitors for effects on GTP hydrolysis using the Transcreener GDP assay (AACR 2025) - "MRTX1133, which binds noncovalently to GDP-bound KRas G12D, inhibited the G12D mutant with an IC50 of 8.4 nM, and was less potent with the G12V and WT enzymes; IC50 = 48 nM and 69 nM, respectively. We note that these GTPase assays require nanomolar concentrations of protein, and therefore cannot be used to accurately determine the potency of covalent inhibitors, such as sotorasib, that bind with picomolar affinity. However, for non-covalent inhibitors, such as MRTX1113 and BI-2865, measuring GTPase activity is a robust approach for selectivity profiling and may yield mechanistic insights different from those gleaned from guanine nucleotide binding/release assays or biophysical methods, e.g. SPR."

Oncology • KRAS

A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance (AACR 2025) - "Growth assays involving direct comparison of ADT-007 with mutant-specific KRASG12C inhibitors (sotorasib), pan-KRAS inhibitors (BI-2865), or other pan-RAS inhibitors (RMC-6236) revealed more complete cancer cell killing by ADT-007. Finally, cancer cell lines resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007 but showed resistance to MRTX849 and MRTX1133, respectively. These results show the unique advantages of ADT-1004 over mutant-specific KRAS, pan-KRAS, and other pan-RAS inhibitors to escape resistance that limits the efficacy of RAS inhibitors FDA-approved or in clinical trials."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRAF • EGF • KRAS

Identifying resistant mechanisms to direct KRAS inhibitors in NSCLC (AACR 2024) - "Recent breakthroughs, however, have resulted in the development of covalent inhibitors capable of selectively targeting the KRAS G12C mutation, like Sotorasib (AMG510) and Adagrasib (MRTX849) which are approved by the FDA due to their encouraging effects in clinical trials. The identification of selective inhibitors of other oncogenic KRAS alleles, such as the noncovalent KRAS-G12D inhibitor, MRTX1133, and a pan-KRAS-inhibitor drug (BI2865) is also a promising next step in the treatment of KRAS-dependent malignancies...We are also trying to identify alterations in the tumor immune microenvironment upon combination therapy targeting KRAS and TEAD. Successful completion of this research will help address the urgent need to understand ways to overcome resistance to KRAS inhibitors and increase their clinical efficacy."

Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TEAD1 • YAP1