Undisclosed CDK4/6 inhibitor / CS Group - LARVOL DELTA

Preclinical Modeling of CDK4/6 Inhibitor and Endocrine Therapy Resistance in ER+ Metastatic Breast Cancer Using Patient-Derived Xenografts (SABCS 2025) - "To evaluate drug response, PDXs were treated with CDK4/6i (Ribociclib or Abemaciclib) in combination with ET (Letrozole + ovariectomy or the oral SERD Elacestrant). PDX models derived from ER+ MBC patients constitute a valuable preclinical platform to explore both intrinsic and acquired resistance to CDK4/6i+ET. These models not only recapitulate clinical phenotypes but also enable the identification of predictive biomarkers and the testing of targeted therapies. Our study provides mechanistic insights and supports the use of PDXs to develop personalised treatment strategies aimed at overcoming resistance in hormone receptor-positive metastatic breast cancer."

Metastases • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • NOTCH2

Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition (SABCS 2025) - "While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit...Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor)...Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib...Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent..."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • CCNE1 • CDK2

Identification of biomarkers of response and the mechanism of action of a selective androgen receptor modulator in estrogen receptor-positive breast cancer patient-derived xenografts (EORTC-NCI-AACR 2024) - "Adding the CDK4/6 inhibitor palbociclib enhanced the antitumor activity of EP0062 or fulvestrant in ESR1-mutant models but not in HER2-enriched or PTEN-mutant PDX models...EP0062 triggers an E2F1 downmodulation which mediates a potent antiproliferative activity. For EP0062-resistant tumors that remain ER-driven, the addition of palbociclib displays a potent antitumor effect."

Biomarker • Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AR • E2F1 • ER • FOXA1 • GATA3 • HDAC2 • HER-2 • PIK3CA • PTEN

THE MULTIKINASE CDK4/6 INHIBITOR NARAZACICLIB OVERCOMES BTK-I RESISTANCE IN MANTLE CELL LYMPHOMA BY TARGETING USP24-P53 SIGNALING AXIS (EHA 2024) - "Aims: Our aim was to compare the efficacy and safety profiles of narazaciclib with three health authority-approvedCDK-i (palbociclib, abemaciclib and ribociclib), as monotherapy or in combination with covalent (ibrutinib,acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTK-i, across a panel of preclinical models of MCLwith distinct sensitivity to these latter, and to determine the molecular bases of the interaction between thesetwo classes of drugs. Our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL,including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitroand in vivo, accelerating cell cycle blockade and, specifically in the BTK-resistant cases, promoting thephosphorylation of USP24, followed by the activation of P53 and the modulation of DNA repair pathway."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Targeted Protein Degradation • CDKN1A

Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers. (PubMed, Mol Cancer Ther) - "FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation...Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors...Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • KRAS

The NEOLETRIB trial: neoadjuvant treatment with Letrozole and Ribociclib in ER-positive, HER2-negative breast cancer. (PubMed, Future Oncol) - P2 | "However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment.Trial registration number: NCT05163106 (ClinicalTrials.gov)."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i) (SABCS 2023) - "All had prior palbociclib + ET (2 pts had abemaciclib or ribociclib after palbociclib); a majority received fulvestrant (67%) and prior chemotherapy (50%). RGT-419B, with potent selective CDK4 activity, CDK2 activity and CDK6 selectivity, demonstrated a favorable safety and PK profile in an ongoing phase I study, with no grade 3 or higher TRAEs observed thus far. RGT-419B administered as once daily monotherapy also demonstrated preliminary evidence of efficacy as well. Dose expansions of RGT-419B as a single agent and in combination with ET in pts with HR+/HER2- ABC following prior CDK4/6i progression are planned."

Clinical • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK2 • HER-2

ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial (SABCS 2023) - P2 | " DNADX was evaluated centrally in available baseline plasma ctDNA samples from PARSIFAL trial (NCT02491983) which randomized 486 patients (pts) with HR+/HER2- advanced breast cancer to receive (1:1 ratio) first line palbociclib with either fulvestrant or letrozole. Liquid biopsy-based DNADX subtypes predict outcomes in pts with HR+/HER2- advanced breast cancer on endocrine therapy and CDK4/6 inhibitors, potentially identifying the most optimal endocrine treatment for each pt."

Circulating tumor DNA • Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

The next-generation oral selective estrogen receptor degrader camizestrant (AZD9833) suppresses ER+ breast cancer growth and overcomes endocrine and CDK4/6 inhibitor resistance. (PubMed, Cancer Res) - "Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination...The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad anti-tumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PIK3CA

Prolonged cell cycle arrest by the CDK4/6 antagonist narazaciclib restores ibrutinib response in preclinical models of BTKi-resistant mantle cell lymphoma (ICML 2023) - "Previous studies have suggested that narazaciclib (ON123300), a second-generation, orally bioavailable and clinical-stage CDK4/6 inhibitor (CDKi), may trigger cell cycle arrest and significant tumor growth inhibition (TGI) in BTKi-resistant MCL models...When combined with ibrutinib, but not with the second generation therapeutic acalabrutinib, narazaciclib achieved significant synergistic antitumor activity in both BTK-sensitive and BTK-resistant cells... Narazaciclib, due to its completely distinct MoA from BTKi involving the direct modulation of the cell cycle, can achieve significant synergistic activity with ibrutinib in vitro and in vivo, especially in BTKi-resistant models of MCL. Ongoing phospho-proteomics and genetic edition assays will help deciphering the molecular bases of this unique drug cooperation at the cell cycle level. Encore Abstract - previously submitted to AACR 2023"

Preclinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDK4 • CDKN1A

Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design. (PubMed, ACS Med Chem Lett) - "Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors...Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 (23) accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 (23) demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer. (PubMed, Nat Commun) - "To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts...More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types."

Circulating tumor DNA • Journal • Metastases • Breast Cancer • Eye Cancer • Hormone Receptor Breast Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • ER

Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models. (PubMed, Sci Rep) - "Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER + breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PIK3CA

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER breast cancer. (PubMed, Nat Commun) - "Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies."

Biomarker • Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PIK3CA • RB1