- |||||||||| 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.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci, Ibrance (palbociclib) / Pfizer, Avastin (bevacizumab) / Roche
Leveraging ChatGPT for literature-based inference of drug-gene relationships in cancer (Section 35) - Mar 5, 2024 - Abstract #AACR2024AACR_4847;
In summary, this pilot research serves as a foundational step towards the utilization of large language models in the field of drug discovery and development. Our ongoing efforts involve the rigorous evaluation of our approach across a diverse spectrum of drug targets and cancer types, as well as the optimization of prompts through state-of-the-art prompt engineering techniques.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, EMD Serono, Vectibix (panitumumab) / Amgen
Comparative spatial transcriptomic analysis of monoclonal antibodies targeting the same molecule: A comparison between cetuximab and panitumumab (Section 34) - Mar 5, 2024 - Abstract #AACR2024AACR_4806;
In the examination of the distribution patterns of two distinct therapeutic antibodies targeting EGFR within cancer tissues, a notable observation was made: while the cell types exhibited similarity, the associated genes demonstrated divergence, with different degrees of alignment with the intended target. This analytical approach, scrutinizing the distribution of different antibodies within tissue sharing a common target, holds promise as a widely applicable method for elucidating divergent therapeutic effects.
- |||||||||| Imlygic (talimogene laherparepvec) / Amgen
Oncolytic hsv-1(vc2) gm-csf regulates the proinflammatory profile suggestive of an immunomodulatory effect in PDAC cells (Section 11) - Mar 5, 2024 - Abstract #AACR2024AACR_4724;
Although 5-fluorouracil or gemcitabine-based chemotherapy is considered as standard of care, harnessing immunological pathways may potentially convert PDAC to a "hot" tumor, thereby providing survival advantage to patients...The FDA approval of T-VEC for the treatment of stage IIIB/IV melanoma validates the preceding argument...Based on the evidence presented here, it is speculated that VC2GM-CSF-induced proinflammatory profile in KPC and Mia PaCa-2 cells converts to an immunomodulatory one characterized by the regulation of FasL and PD-L1. The effect of VC2GM-CSF in a PDAC organoid model to understand the interplay between the tumor and the stromal cells in response to the virus is currently underway.
- |||||||||| Stivarga (regorafenib) / Bayer
Establishing a novel clinically relevant disease model of glioblastoma (Section 6) - Mar 5, 2024 - Abstract #AACR2024AACR_4629;
We have shown the model is markedly insensitive to intervention with chemotherapy and immune checkpoint therapy, mirroring what is seen clinically in patients. The model may therefore be employed in future pre-clinical studies to guide clinical trials in the setting of mesenchymal GBM.
- |||||||||| 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.
- |||||||||| Ibrance (palbociclib) / Pfizer
A homogeneous assay system for discernment of proliferative, antiproliferative, and cytotoxic effects in culture (Section 13) - Mar 5, 2024 - Abstract #AACR2024AACR_4241;
Notably, there was no cytotoxicity detected at the tested doses and treatment duration (up to 48 h), but a significant reduction in viable cell number at maximal palbociclib concentrations, aligning with an antiproliferative mechanism. This work establishes a rapid, simple, luminescent assay for determining Ki-67 levels that can be paired with a fluorogenic readout of cell death, facilitating efficient and quantitative discernment of altered proliferation in mammalian cell culture using standard microplate readers.
- |||||||||| 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
- |||||||||| Ibrance (palbociclib) / Pfizer
A novel RB1 E3 ligase TRIM37 contributes to palbociclib resistance in breast cancer (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_3987;
Our study also suggests that high expression of TRIM37 mediated by AR activation could deplete RB1, which is the target of Palbociclib, eventually leading to resistance. These findings are supportive of the contribution of AR activation to Palbociclib 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.
- |||||||||| atirmociclib (PF-07220060) / Pfizer
Preclinical development of the CDK4 selective inhibitor PF-07220060: Increased CDK4 versus CDK6 inhibition leads to improved anti-tumor efficacy at therapeutic concentrations (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_2718;
PF-07220060 is a selective inhibitor of CDK4, displaying ~20-fold and ~4-fold increased selectivity for CDK4 versus CDK6 when compared to palbociclib and abemaciclib/ribociclib, respectively...PF-07220060 sensitizes HR+ HER2- breast cancer to the estrogen inhibitor, fulvestrant and the degrader, ARV-471 (vepdegestrant)...Similarly, PF-07220060 sensitizes prostate cancer to the androgen receptor antagonist, enzalutamide...Further addition of the PI3K inhibitor alpelisib was sufficient to enforce tumor shrinkage in vivo...Even so, in these instances, PF-07220060's efficacy remained comparable to palbociclib's when both drugs were used at their therapeutic doses. We conclude that PF-07220060's anti-tumor efficacy is broadly superior to currently approved dual CDK4/6 inhibitors.
- |||||||||| GSC000190 / GeneScience
GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_2693;
In an HGSOC PDX model which is resistant to platinum and olaparib, GSC000190 induced strong tumor regression both as single agent and through combination without significant body weight reduction...GSC000190 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GSC000190 is now under IND-enabling study and P1 study is planned in the second quarter of 2024.Legal entity responsible for the study: The authors.Disclosure: All authors have declared no conflicts of interest.
- |||||||||| 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.
- |||||||||| Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_2576;
The CXCR4 inhibitor plerixafor is used to increase mobilization of peripheral blood stem cells in combination with filgrastim...These have included use of plerixafor with 7+3 or MEC, BL-8040 with cytarabine, and ulocuplumab with MEC...The objective of this preclinical study is to identify the AML patient population most likely to respond to CXCR4 inhibition, and the role of combined beta-adrenergic blockade, as the latter has been shown pre-clinically to augment mobilization of HSCs when combined with a CXCR4 inhibitor, GPC-100 (Sukhtankar et al... These studies support further investigation of whether simultaneous blockade of CXCR4 and ADBR2 may potentiate chemotherapy response in AML by limiting microenvironment mediated chemotherapy protection and reveal that patients with new diagnosis may be more susceptible to this approach.
- |||||||||| 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.
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