- |||||||||| 5-fluorouracil / Generic mfg.
The MTA-cooperative PRMT5 inhibitor AM-9747 exhibits robust antitumor activity in combination with clinically relevant chemotherapies and targeted agents in MTAP null tumor models (Section 19; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_8449;
AMG 193, currently in Phase 1 trials, and its representative analog AM-9747 have broad spectrum activity in MTAP null tumor models across hematologic and solid tumor indications...SOC agents representing a variety of mechanisms of action (paclitaxel, carboplatin, gemcitabine, pemetrexed, irinotecan, 5-FU) were evaluated and results ranged from strongly synergistic (CI<0.3) to additive (CI=1) in a panel of non-small cell lung carcinoma (NSCLC) and pancreatic cancer cell lines...To target both pathways we combined the FDA-approved KRAS G12C inhibitor sotorasib with AM-9747 and observed synergy (CI<0.6) in MIAPACA2 cells...This combination is being tested in additional MTAP null KRAS G12C mutant models. Overall, our data suggests that combining MTA-cooperative inhibitor AM-9747 with SOC or clinically relevant targeted agents is a compelling therapeutic strategy for the treatment of MTAP null cancers.
- |||||||||| adavosertib (AZD1775) / AstraZeneca, Lumakras (sotorasib) / Amgen
Targeting WEE1 to improve the therapy of KRAS G12C mutant non-small cell lung cancer (Room W224 - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_7888;
We identify AZD1775, a WEE1 inhibitor, as a novel combination candidate, which enhanced the anti-tumor activity of sotorasib both in vitro and in vivo preclinical models. These findings can lead to a novel therapeutic strategy for KRAS G12C mutant NSCLC.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
A novel ex vivo platform, 3D-EXpress, to rapidly assess the efficacy of KRAS targeting drugs alone and in combination with nivolumab using a biorepository of fresh patient tumoroids with intact tumor microenvironment (Section 2; Poster Board #22) - Mar 14, 2023 - Abstract #AACR2023AACR_7713;
3D tumoroids were treated with vehicle only, a SOS1::KRAS inhibitor, BI 1701963, apotent, selective, and covalent KRASG12C inhibitor, MRTX849, and a KRAS G12C inhibitor, sotorasib,alone and in combination with nivolumab for 72h. Our data demonstrate that the 3D-Express platform, using cryopreserved 3D tumoroidswith intact TME, is an effective tool to assess the efficacy of KRAS and immune checkpoint inhibitorstargeting drugs to identify rational combination therapies and to develop clinically relevant biomarkersfor individualized patients in the future.
- |||||||||| Lumakras (sotorasib) / Amgen
B6-KrasLSL-G12C mouse model for assessing the occurrence and development of lung and pancreatic cancer tumors (Section 25; Poster Board #18) - Mar 14, 2023 - Abstract #AACR2023AACR_7481;
Our data demonstrate that the 3D-Express platform, using cryopreserved 3D tumoroidswith intact TME, is an effective tool to assess the efficacy of KRAS and immune checkpoint inhibitorstargeting drugs to identify rational combination therapies and to develop clinically relevant biomarkersfor individualized patients in the future. In May 2021, the FDA approved sotorasib (Lumakras
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen
Integrated platform enables KRAS-targeted drugs discovery (Section 16; Poster Board #30) - Mar 14, 2023 - Abstract #AACR2023AACR_7322;
In addition, we developed a panel of resistant models to KRAS G12C inhibitor that bringing a better understanding of the biological basis of drug resistance, and will serve as a new tool to optimize KRAS-G12C inhibitor regimens and combinatorial strategies. The comprehensive KRAS-targeted drug discovery platform is empowering new drug research and development.
- |||||||||| Lumakras (sotorasib) / Amgen
Taking sotorasib with an acidic beverage improves sotorasib exposure for subjects on omeprazole (Section 47; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_7113;
Compared to the geometric mean ratio of sotorasib and omeprazole taken with water, taking sotorasib and omeprazole with an acidic beverage resulted in an increase of 19.0 percentage-point in AUClast and a 24.6 percentage-point increase in Cmax. Coadministration of sotorasib and omeprazole with Coca Cola was safe and well tolerated.For patients on acid-reducing drugs, sotorasib taken with an acidic beverage is an effective strategy to increase sotorasib exposure and counteract the reduced exposures resulting from the drug-drug interaction effect of acid-reducing drugs.
- |||||||||| Krazati (adagrasib) / Mirati, Fyarro (nanoparticle albumin-bound rapamycin) / Aadi Biosci, Lumakras (sotorasib) / Amgen
Synergistic antitumor activity of nab-sirolimus in combination with KRAS inhibitors (KRASis) sotorasib and adagrasib in KRAS G12C NSCLC and bladder cancer xenografts (Section 38; Poster Board #2) - Mar 14, 2023 - Abstract #AACR2023AACR_7068;
A multicenter, single-arm, open-label Phase 1/2 clinical study is planned to determine the recommended Phase 2 dose, safety, tolerability, and efficacy for the combination of ada and nab-s in patients with KRAS G12C tumors. $$table_{D2CC43B4-19F7-4EEF-B479-9D4337036322}$$Changes in TGI and Tumor RegressionTumor ModelCombination TreatmentTGI vs Single Agent (%)P Value vs Single Agent for Tumor Growth Curve (ANOVA)Tumor Regression Over 30%P Value vs Single Agents for Rate of Tumor Regression Over 30% (Chi-Square)vs nab-Svs KRASivs nab-Svs KRASiNCI-H2030nab-S + Sotorasib1291110.010.0013/60.03NCI-H2122nab-S + Sotorasib1121060.001<0.0018/10<0.001nab-S + Adagrasib1011000.001<0.0014/100.03UMUC3nab-S + Sotorasib107105<0.001<0.0016/6<0.001nab-S + Adagrasib107107<0.0010.046/60.001ANOVA, analysis of variance; KRASi, KRAS inhibitor; nab-s, nab-sirolimus; TGI, tumor growth inhibition.
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen
Overcoming KRAS G12C inhibitor resistance with a chaperone-mediated protein degrader (CHAMP) (Section 34; Poster Board #6) - Mar 14, 2023 - Abstract #AACR2023AACR_6726;
Furthermore, in vivo treatment with RNK07421 demonstrated dramatic tumor growth inhibition as compared to adagrasib treatment alone. Together, these observations indicate that the novel mechanisms of action of RNK07421 may provide several advantages over G12C inhibitors and possibly other targeted protein degradation agents to effectively treat KRAS G12C-dependent NSCLC.
- |||||||||| ICP-189 / InnoCare
Preclinical development of SHP2 allosteric inhibitor ICP-189 (Section 20; Poster Board #9) - Mar 14, 2023 - Abstract #AACR2023AACR_6202;
ICP-189 is a novel allosteric inhibitor of SHP2 with broad-spectrum anti-tumor activities as a single agent or in combination with other targeted or immune modulating anti-cancer therapeutics. ICP-189 is now in phase I clinical trial in China and United States.
- |||||||||| Lumakras (sotorasib) / Amgen
Developing cancer cell based in vitro and in vivo models with CRISPR-mediated knock-in technology for anti-tumor drug discovery (Section 18; Poster Board #26) - Mar 14, 2023 - Abstract #AACR2023AACR_6189;
Herein, by employing CRISPR/Cas9 system, two human cancer cell line-based, inheritable drug resistance models were established where the mutation site C481S of BTK in REC-1 conferred resistance to Ibrutinib and the mutation site R537S/D538G of ESR1 exerted resistance to Fulvestrant in MCF-7...The resultant KRASG12C CT26 cell line showed pronounced inhibitory effect after treatment with AMG510...Based on HiBiT protein tagging technology, we generated a series of HiBiT knock-in cell lines for real-time cell-based protein degradation analysis on various compelling targets, such as ESR1, KRAS, and BRD4, et al. Thereby, the construction of these in vitro and in vivo models with the ease of CRISPR KI technology is indispensable in new generation of therapeutic drug exploration.
- |||||||||| Lumakras (sotorasib) / Amgen
KRAS G12C mutant allele amplification drives resistance to sotorasib in vitro (Section 15; Poster Board #21) - Mar 14, 2023 - Abstract #AACR2023AACR_6096;
In comparison to DMSO-treated and parental controls, the sotorasib-resistant NCI-H358 cells contained an approximately 50-fold increase in KRAS G12C mutant allele copy numbers.Preclinical data generated using a KRASG12C inhibitor-resistant lung cancer cell line is consistent with clinical observations of acquired KRAS amplification following KRASG12C inhibitor treatment as a mechanism of resistance. This model further provides an opportunity to study acquired KRAS amplification and investigate combination treatment options in vitro.
- |||||||||| Krazati (adagrasib) / Mirati, opnurasib (JDQ443) / Novartis, Lumakras (sotorasib) / Amgen
Chromatin modification driving sub-clonal resistance to KRAS G12C combination therapies in KRAS mutant non-small cell lung cancer (Section 15; Poster Board #17) - Mar 14, 2023 - Abstract #AACR2023AACR_6092;
Moreover, we observed distinct persister subpopulations with resistance to KRAS G12Ci combination co-targeting orthogonal pathways (SHP2, CDK4/6, PI3K, and MCL-1), raising the possibility that distinct epigenetic-transcriptional states contribute to differential drug response and clonal evolution of persisters. Collectively, these results suggest that more complete tumor regression may be achieved by orthogonal strategies that target different resistant populations within the same tumor.
- |||||||||| Lumakras (sotorasib) / Amgen
Discovery of GSTZ1 as a novel target for drug refractory non-small cell lung cancer by using fragment-based chemical proteomics (Section 14; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_5787;
Using sotorasib-refractory KRAS G12C H1792 lung cancer cells, we identified 932 probe-enriched proteins from panel-wide cross-comparisons suggesting the high potential of exploring the ligandable proteome...We developed a chemical biology workflow for the simultaneous discovery of high-confidence targets and their binding probe molecules, such as probe 17 and GSTZ1. GSTZ1 was found to cooperate with oncogenic alterations in supporting refractory NSCLC cell survival signaling, which may form the biological basis for developing novel GSTZ1 inhibitors to improve the therapeutic efficacy of oncogene-directed targeted drugs.
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen
Molecular determinants of KRAS p.G12C inhibitor efficacy in advanced NSCLC (Room W414 - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_5535;
Co-mutations in KEAP1, SMARCA4 and CDKN2A/2B define subgroups of KG12C NSCLC pts with markedly distinct outcomes with KG12Ci monotherapy. Tailoring of KG12C inhibitor-anchored therapeutic strategies and patient stratification should take into account the co-mutation status of individual tumors.
- |||||||||| Lumakras (sotorasib) / Amgen
Increasing the efficacy of KRASG12Cinhibitor therapy through the adjuvant use of FAP targeted radiotherapy in a murine model of lung cancer (Section 19; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_5034;
Animals were implanted with KRASG12C heterozygote LLC1 lung cancer cells and treated according to the following groups: untreated control, sotorasib treatment, 177Lu-FAPI-04 treatment, and combined treatment...Effects are mediated through decreased cell cycling, increased apoptotic cell death, and changes in key cell signaling pathways. Future translational studies will assess this therapy combination in patients to evaluate its ability to increase response to therapy.
- |||||||||| Lumakras (sotorasib) / Amgen
DNA replication stress and mitotic catastrophe mediate sotorasib addiction in KRASG12C-mutant cancer (Section 20; Poster Board #6) - Mar 14, 2023 - Abstract #AACR2023AACR_4977;
Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal in sotorasib-resistant cancer cells in vitro and in vivo. Collectively, we identified the sotorasib addiction phenomenon in cancer cells, determined the underlying mechanisms of replication stress and mitotic catastrophe, and provide a novel therapeutic strategy against sotorasib-addicted cells with pharmacological enhancement of aberrant MAPK activation with a type I BRAF inhibitor, which can more effectively restrained cell growth both in vitro and in vivo.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
The combination of ulixertinib (ERK1/2 Inhibitor) and KRASG12C inhibition demonstrates significant efficacy in preclinical models (Section 14; Poster Board #28) - Mar 14, 2023 - Abstract #AACR2023AACR_4914;
Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups.In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated.
- |||||||||| Synergism between inhibitors of the EGFR-RAS-RAF-MEK pathway and the WNT pathway (Section 46; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_4815;
P1b
Secondary endpoints included PK, overall response rate, CR and PR rate, and duration of response by RECIST 1.1 and irRECIST 1.1. The clinical protocol and available data of CGX1321 in combination with encorafenib and cetuximab in CRC patients with RSPO fusions and BRAFV600E mutations will be discussed.
- |||||||||| Lumakras (sotorasib) / Amgen
Two detection methods of clinical KRAS G12C mutation detection for companion diagnostics (Section 41; Poster Board #6) - Mar 14, 2023 - Abstract #AACR2023AACR_4552;
The FDA approved sotorasib, a KRAS G12C inhibitor, for targeted treatment of patients with KRAS G12C-mutated locally or metastatic non-small cell lung cancer (NSCLC)...Our methods are especially valuable for labs that appreciate simple, economical, yet sensitive companion diagnostics assays for KRAS G12C mutation. QClamp
- |||||||||| Lumakras (sotorasib) / Amgen
KRAS mutant gene editing prevents tumor growth in vivo and overcomes acquired resistance to KRASG12C inhibitor (Section 20; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_3711;
We showed, that ADGN-123 containing gRNAG12C can effectively reduce the proliferation and inhibit ERK and AKT phosphorylation of AMG-510 acquired resistance cells and that no resistance occurs after ADGN-123 treatment...Our study provides a proof-of-concept that ADGN can be applied to target driver mutations of cancers in vivo and permanently disrupt the oncogenic alleles, leading to major tumor regression. ADGN-123 can be used as a strategy to overcome resistance associated to small molecule inhibitors of KRASG12C.
- |||||||||| FMC-376 / Frontier Medicines
Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C (Room W224 - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_3158;
Further evaluation of FMC-376 in vivo has demonstrated rapid and durable KRASG12C target occupancy (>90%) and pathway inhibition in tumors, resulting in regression of CDX/PDX tumor models. FMC-376, an inhibitor of both active and inactive forms of KRASG12C, provides a differentiated mechanism of action with the potential for broader and more durable response in the clinic.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Gilotrif (afatinib) / Boehringer Ingelheim, Lumakras (sotorasib) / Amgen
Global mapping of pathway modules and phosphorylation networks in PDX and corresponding organoid (PDXO) models treated with targeted therapies (Section 7; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_2998;
Based on previous data, a specific relationship between area under the curve (AUC) value of organoid drug dose response and in vivo tumor growth has been observed, irrespective of the drug treatment. The predictivity of organoid cultures was demonstrated to model in vivo drug responses and also to serve as a powerful platform to investigate target identification, mechanism of action and resistance mechanism via functional proteome and phospho-proteome analysis.
- |||||||||| Krazati (adagrasib) / Mirati, MRTX1133 / Mirati, Lumakras (sotorasib) / Amgen
BaF3 RAS cell panel, a powerful cell model for Ras inhibitor discovery and development (Section 1; Poster Board #26) - Mar 14, 2023 - Abstract #AACR2023AACR_2959;
In addition to use the cell lines for in vitro assays, the transformed Ba/F3 lines can grow well in immune-deficient mice as in vivo models. Our data indicate that the cell line panel of Ba/F3 is a powerful system for new RAS inhibitor discovery and development.
- |||||||||| Lumakras (sotorasib) / Amgen
CDX model based genome-scale CRISPR KO screens for modulators of KRAS (G12C) inhibitor sensitivity (Section 9; Poster Board #21) - Mar 14, 2023 - Abstract #AACR2023AACR_2783;
Genomic DNA was extracted from both baseline cell samples and tumor samples followed by Next-generation sequencing. We have performed QC analysis for all the samples and will discuss the hits from the screen and their implication in AMG 510-induced cancer sensitivity and resistance.
- |||||||||| RGT-018 / Regor
Discovery of RGT-018: A potent, selective and orally bioavailable SOS1 inhibitor for mutant KRAS-driven cancers (Section 17; Poster Board #8) - Mar 14, 2023 - Abstract #AACR2023AACR_2538;
FDA currently approved sotorasib provides breakthrough therapy for cancer patients with KRASG12C mutation, however there is still high unmet medical need for new agents that target a broader KRAS mutated tumors. The pharmacological properties of RGT-018 represent an attractive drug candidate with oral bioavailability for combination with targeted agents to treat a broader patient population driven by mutant KRAS.
- |||||||||| JSI-1187 / JS InnoPharm, VIC-1911 / VITRAC Therap
Efficacy of JSI-1187 or VIC-1911 in combination with KRAS G12C inhibitors for the treatment of KRAS G12C-mutated non-small cell lung cancer and colorectal cancer (Section 15; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_2525;
Additionally, the antitumor growth effect of JSI-1187 and sotorasib was significantly better than the combination of the MEK inhibitor, trametinib, and sotorasib...In addition, the combination of JSI-1187 and sotorasib demonstrated a significant increase in tumor growth inhibition in a CRC PDX model. Taken together, our preclinical studies suggest that the combination of an ERK inhibitor, JSI-1187, or an AURKA inhibitor, VIC-1911, may potentially overcome the primary resistance and prevent or delay the acquired resistance to G12C inhibitors.
- |||||||||| veliparib (ABT-888) / AbbVie, Lumakras (sotorasib) / Amgen
p53 rescue of tumor suppressor function with ADGN-531 causes tumor regression both as single agent and in combination with PARPi and KRASG12Cinhibitors (Section 19; Poster Board #17) - Mar 14, 2023 - Abstract #AACR2023AACR_2407;
We demonstrated that ADGN-531 mediated p53 rescue markedly improves (200 fold) and restores the sensitivity of ovarian and breast cancer cells to Veliparib...ADGN-531 is effective in rescuing P53 functions both in vitro and in vivo. Our study provides a proof-of-concept that restoration of tumor suppressor function by ADGN-531 could be used as a single agent therapy or in combination together with other therapies for potent combinatorial cancer treatment.
- |||||||||| MRTX1133 / Mirati, Lumakras (sotorasib) / Amgen
Characterization of the selective inhibitory effect of KRas inhibitors in different cellular assay formats (Section 19; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_2406;
These results indicate that the described cellular pERK AlphaLisa assay established for selected cancer cell lines could be a useful tool to screen newly developed KRas inhibitors for their selective inhibition of specific KRas mutants. Additionally, the application of not only 2D proliferation but also 3D growth studies can further characterize the inhibitory potential of these KRas inhibitors.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance (Section 43; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_2317;
In another example, tipifarnib has been demonstrated by others to inhibit the ability of tumor cells to enter a drug-tolerant state induced by the EGFR inhibitor, osimertinib, in EGFR-mutant NSCLC models...We have conducted in vitro 2D and 3D viability and regrowth experiments using combinations of tipifarnib with KRAS G12C inhibitors and have observed synergistic, anti-proliferative effects in KRAS G12C NSCLC cell lines as well as enhanced activity of combination in a KRAS G12C NSCLC PDX model. We are currently expanding the scope of in vitro and in vivo combination studies to further evaluate the molecular mechanism(s) of resistance that tipifarnib targets when combined with KRAS G12C inhibitors.
- |||||||||| Lumakras (sotorasib) / Amgen
Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines (Section 43; Poster Board #22) - Mar 14, 2023 - Abstract #AACR2023AACR_2316;
The combination of metformin with sotorasib showed synergic effects on cytotoxicity, increased apoptosis induction, and a remarkable inhibition of downstream proteins involved in the signaling of growth factor receptors in all tested cells. Moreover, these results suggest a sensitizing effect of metformin to sotorasib treatment in cells without KRAS mutations, such as H522.
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