- |||||||||| MRTX1133 / BMS, Lumakras (sotorasib) / Amgen
In vivo and in vitro experience with novel direct Pan-RAS inhibitors (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5472;
They exhibit distinct RAS signal inhibition patterns compared to these agents. They can also co-operate with the clinical agents and reduce drug resistance effects.
- |||||||||| Krazati (adagrasib) / BMS, CYRS1645 / Yuhan Corp, Lumakras (sotorasib) / Amgen
Discovery of a potent, selective, and orally available small molecule for disruption of the SOS1-RAS interaction (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5465;
It has demonstrated remarkable synergy effects with RTK/RAS/MAPK pathway inhibitors, significantly impeding the growth of tumors carrying KRAS or EGFR mutations in vivo. Overall, our development candidate has demonstrated significant therapeutic potential in combination with inhibitors targeting the RTK/RAS/MAPK pathway for cancers bearing activating mutations in this pathway.
- |||||||||| MRTX1133 / BMS, Lumakras (sotorasib) / Amgen
The in vivo Hollow Fiber model is a valuable tool in drug development of selective KRas inhibitors (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_5269;
AMG510 (Sotorasib), a drug approved for tumors with a G12C Kras mutation, and MRTX1133, which is currently in clinical phase and shows activity in tumors with a G12D Kras mutation, were screened for their inhibitory effect on the pancreatic tumor cells MiaPaCa-2 (G12C Kras mutation), AsPC-1 (G12D Kras mutation) and BxPC-3 (wt Kras) in the in vivo Hollow Fiber model in female NMRI nude mice. While the growth of BxPC-3 tumor cells was not affected by either inhibitor, the growth of AsPC-1 tumor cells in particular was selectively and significantly inhibited by MRTX1133.In summary, the in vivo Hollow Fiber model is a fast and cost-effective model that can play an prominent role in drug development as a link between in vitro and in vivo xenograft studies by providing rapid and transferable evidence for in vivo efficacy.
- |||||||||| OncoKB (Section 36) - Mar 5, 2024 - Abstract #AACR2024AACR_4864;
Lastly, noting emerging data with the KRAS G12X-specific inhibitor, RMC-6236, OncoKBTM included all alleles at KRAS position G12 as Level 4.In sum, six novel clinically actionable biomarkers (all Level 1) and 14 follow-on precision oncology therapies for existing leveled biomarkers were added to OncoKBTM in the past year. OncoKBTM's current focus includes coverage of additional cancer-associated genes, annotation of germline alterations and incorporation of OncoKBTM data into an electronic health record system.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Targeting lipid metabolism disrupts KRAS oncogenesis in pancreatic cancer (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_4263;
Since various KRAS mutants require unsaturated PS to propagate signaling, our approach targets diverse KRAS mutants, uniquely addressing drug resistance issue. Further, we will optimize the LPCAT3 inhibitors and study their efficacy in xenograft mouse models.
- |||||||||| Lumakras (sotorasib) / Amgen
Elucidating the mechanisms of acquired resistance to AMG510 in cancer models harboring KRAS G12C mutations (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4032;
Upon comparison of sensitive parental tumors and resistant tumors, we found that highly expressed KRAS and constant activation of RAS-MAPK signaling pathway are critical for resistant tumor progression following AMG510 treatment. In addition, resistant tumor cells are responsible for the elevated secretion of CXCL2/3/5, which dramatically reconditions the tumor immune microenvironment and recruits immunosuppressive cells.In summary, the exploration of the resistance mechanism in AMG510-induced resistant models provides insight into the development of new-generation KRAS-G12C inhibitors and novel combinatorial therapies.
- |||||||||| Characterization of a panel of CRISPR/Cas9 engineered KRAS G12C inhibitor-resistant tumor models (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4028;
CRISPR/Cas9 engineered second site KRAS mutations in cells harboring KRAS G12C mutation displayed a differentially resistant profile to KRAS G12C inhibitors. Thus, H95D/Q/R, R68S and Y96D can be used as preclinical inhibitor-resistant models to evaluate clinical strategies to overcome resistance to KRAS-targeted therapies.
- |||||||||| Krazati (adagrasib) / BMS, MRTX1133 / BMS, Lumakras (sotorasib) / Amgen
Identifying resistant mechanisms to direct KRAS inhibitors in NSCLC (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4026;
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...Among the several proteins whose expressions were altered in the KRAS-inhibitor-resistant cells, we identified the YAP/TEAD1 pathway that was commonly upregulated in the cells resistant to MRTX849 (G12Ci) or MRTX1133 (G12Di)...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.
- |||||||||| KEAP1-NRF2 mediated resistance against KRASG12D inhibitor in pancreatic ductal adenocarcinoma (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4022;
Recently, the clinical candidate KRASG12D-selective inhibitor MRTX1133 (G12Di) has been shown to potently suppress both activation of the RAF-MEK-ERK signaling pathway downstream of KRAS and tumorigenic growth of KRASG12D-mutant PDAC in vitro and in vivo...We further discovered that combination treatment with a glutaminase inhibitor (CB-839) synergistically enhanced G12Di growth suppression not only of KEAP1-knockout but also of parental PDAC cells. In summary, our study establishes a role for KEAP1 loss as a mechanism that drives PDAC resistance to KRAS inhibitors and identifies GLS inhibition as a possible approach to overcome NRF2-driven resistance.
- |||||||||| Krazati (adagrasib) / BMS, Augtyro (repotrectinib) / BMS, Lumakras (sotorasib) / Amgen
The FAK/SRC axis mediates resistance to KRAS G12C inhibitors and its blockade can overcome KRAS inhibitor resistance (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4021;
Overall, our findings indicate that activation of FAK is a key mechanism of adaptive feedback and acquired resistance to KRAS G12C inhibitors in KRAS G12C-positive NSCLC and highlight the therapeutic potential of FAK/SRC inhibitors in combination with KRAS G12C inhibitors. These data support the clinical testing of the combination of FAK/SRC inhibitors and KRAS G12C inhibitors in patients with KRAS G12C-positive NSCLC.
- |||||||||| Mekinist (trametinib) / Novartis, BeiGene, Lumakras (sotorasib) / Amgen
Targeting YAP1/TEAD signaling re-sensitizes MAPK/ERK pathway inhibitors in KRAS- driven cancer cells (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4017;
Moreover, TEADi had almost no impact on ERK phosphorylation in either of the resistant cells, suggesting that re-sensitization of MAPK/ERK pathway inhibitors by TEADi is independent of primary onco-genetic signaling pathway. Taken together, our study demonstrates that inhibition of YAP1/TEAD signaling would be an efficient approach to overcome resistance to MAPK/ERK pathway inhibitors in the patients carrying KRAS mutations, and provides the scientific basis for development of combination therapy strategies.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Combination of KRASG12C and FGFR1 inhibitors as a resistance-overcoming therapeutic strategy for maximizing therapeutic impact of KRASG12C inhibitors (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4016;
Deciphering resistance mechanisms to G12Ci is of prime relevance to predict which patients may benefit from these therapies and to propose resistance-overcoming therapeutic strategies for maximizing therapeutic impact of these inhibitors.MATERIAL AND We generated 10 acquired resistant LUAD cell lines to G12Ci (Sotorasib and Adagrasib), exposing sensitive cells to increasing concentrations of drugs. The activation or overexpression of FGFR1 acts as a mechanism of acquired resistance to KRASG12C inhibitors.-The combination of FGFR and KRASG12C inhibitors is effective as an acquired/intrinsic resistance-overcoming therapeutic strategy in cell lines, PDXDOs and PDXs models.-The combination of FGFR and KRASG12C inhibitors is also synergistic for sensitive models, which could maximize therapeutic impact of KRASG12C inhibitors.
- |||||||||| Lumakras (sotorasib) / Amgen
Acquired resistance to sotorasib in KRASG12C mutant NSCLC is vulnerable to PI3K-mTOR pathway inhibition and regulated by 4E-BP1 (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4015;
Both resistant PDXOs and cell lines showed resistance to adagrasib, another selective, KRASG12C inhibitor...Inhibition of PI3K, AKT and mTOR by copanlisib, MK2206 and everolimus respectively was synergistic with sotorasib in AR cells and PDXOs, with copanlisib being the most effective...When copanlisib was combined with sotorasib in treating the resistant TC303AR, TC314AR PDXs, H358AR CDX and H23AR xenograft tumors, antitumor effects were observed in every model. Inhibition of the PI3K pathway at different nodes is a vulnerability in KRASG12C mutant NSCLC with sotorasib AR and p4E-BP1 is a mediator of sotorasib resistance
- |||||||||| Lumakras (sotorasib) / Amgen
RAS-Bio a unique pan-cancer biobank for RAS-driven tumors (Section 43) - Mar 5, 2024 - Abstract #AACR2024AACR_3644;
RAS-Bio represents a comprehensive biobank of clinical, pathological, and genomic detail in RAS-mutant lung cancers. Optimizing collaborative potential with academia/industry to facilitate prospective sampling of patients at different timepoints and integrating colorectal and pancreas cancers in our protocol.
- |||||||||| taladegib (ENV 101) / Endeavor BioMed, Lumakras (sotorasib) / Amgen, Erivedge (vismodegib) / Roche
Activating PIK3CA mutations and hedgehog signaling may confer resistance to KRAS inhibition in colorectal cancer (Room 5 - Upper Level - Convention Center) - Mar 5, 2024 - Abstract #AACR2024AACR_3380;
Resistance in CRC to KRASG12C inhibitors may be attributed to activated PIK3CA mutations and the Hedgehog signaling pathway. The future study will focus on detailed investigations involving comprehensive transcriptome and exome profiles in tumors and PDX models treated with anti-KRAS drugs in monotherapy and combination therapy.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Pan-RAS inhibition by a tumor-targeted biotherapeutic (Room 15 - Mezzanine Level - Convention Center) - Mar 5, 2024 - Abstract #AACR2024AACR_3326;
Indeed, RASx is effective not only against RAS-addicted tumors, but also wildtype RAS tumors driven by upstream receptor tyrosine kinases, potentially expanding the clinical utility of this platform. RASx is a first-in-class, tumor-targeted pan-RAS inhibitor that represents a unique entry into the growing armamentarium against oncogenic RAS.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Discovery of a novel brain penetrant SHP2 allosteric inhibitor with anti-tumor effects (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_2686;
Furthermore, robust anti-tumor acitivty was confirmed in intracranial brain tumor model, supporting its potential to control brain-metastasized tumors. The present data suggest that KT-01766 is a potential candidate for combination therapy with agents targeting RAS pathway, as it is able to effectively suppress tumor growth both systemically and within the brain in KRAS mutated cancers.
- |||||||||| ADGN-531 / Aanastra
In vivo rescue of p53 tumor suppressor function with ADGN-531 across Pan-p53 alterations (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_2547;
ADGN-531 treatments are well tolerated, no sign of clinical toxicity was detected after single or repeated administrations.ADGN-531 is effective in rescuing p53 function both in vitro and in vivo across a wide range of p53 alterations. Our study provides a proof-of-concept that restoration of tumor suppressor function by ADGN-531 could be used as a single agent therapy in P53 altered tumors independent of other driver mutations e.g., KRAS, or with other therapies for potent combinatorial cancer treatment.
- |||||||||| Tagrisso (osimertinib) / AstraZeneca, Lumakras (sotorasib) / Amgen
Leveraging the IVIS imaging technologies for drug potency testing in orthotopic and metastatic tumor models (Section 45) - Mar 5, 2024 - Abstract #AACR2024AACR_2518;
Our study provides a proof-of-concept that restoration of tumor suppressor function by ADGN-531 could be used as a single agent therapy in P53 altered tumors independent of other driver mutations e.g., KRAS, or with other therapies for potent combinatorial cancer treatment. In this poster, we demonstrate how the IVIS optical imaging technology is employed to determine the effects of two drugs on two tumor models:
- |||||||||| Journal: Tissue factor overexpression promotes resistance to KRAS-G12C inhibition in non-small cell lung cancer. (Pubmed Central) - Feb 26, 2024
P1/2
The recently approved KRASG12C mutation-specific inhibitors sotorasib and adagrasib (KRASG12C-I) represent a promising therapy for KRASG12C-driven non-small cell lung cancer (NSCLC)...Tissue factor (TF) is overexpressed in KRAS-mutated (KRASmut) NSCLC and is the target of the FDA-approved ADC Tivdak...Thus, we have identified the TF/mTORC2 axis as a critical new mechanism for triggering immunosuppression and KRAS-I resistance. We propose that targeting this axis with HuSC1-39 or MTI-31 will improve KRAS-I response in KRAS-driven NSCLC.
- |||||||||| HRX-0233 - HepaRegeniX, Netherlands Cancer Institute / Antoni van Leeuwenhoek, Lumakras (sotorasib) / Amgen
Journal: Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS-mutant cancers. (Pubmed Central) - Feb 24, 2024
We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal: Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions. (Pubmed Central) - Feb 19, 2024
We systematically summarize recent advances in the discovery and optimization processes of direct KRAS inhibitors (including KRAS, KRAS, KRAS and KRAS inhibitors), indirect KRAS inhibitors (SOS1 and SHP2 inhibitors), pan-KRAS inhibitors, as well as proteolysis-targetingchimeras degrades and molecular chaperone modulators from the perspective of medicinal chemistry. We also discuss the current challenges and opportunities of KRAS inhibition and hope to shed light on future KRAS drug discovery.
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