Micaela Morgado

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies. Significance: Acquired resistance may limit the impact of KRAS inhibition in patients with PDAC. Using clinical samples and multiple preclinical models, we define heterogeneous genetic and non-genetic mechanisms of resistance to KRAS inhibition that may guide combination therapy approaches to improve the efficacy and durability of these promising therapies for patients. See related commentary by Marasco and Misale, p. 2018.

Successfully extending immunotherapies to solid tumors involves addressing several key challenges, importantly the “antigen dilemma”, the expression of a solid tumor target antigen on the normal tissue of tumor origin. Claudin 18.2 (CLDN18.2) has emerged as an important target for upper gastrointestinal (GI) cancer therapies (such as Zolbetuximab, a naked antibody, recently approved; or CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy with promising clinical data). However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041. Here, we describe clinical Zolbetuximab treatment associated cases of gastric erosive lesions. We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy. Claudin 18.2 (CLDN18.2) has emerged as a target for gastrointestinal cancer, however, on-target/off-tumor toxicities have been also reported. Here, after reporting evidence of erosive gastritis in patients treated with CLDN18.2 targeted immunotherapies, the authors develop and characterize CLDN18.2 fully-human VH-only single domain CARs, showing that a lower affinity CAR mitigates on-target/off-tumor toxicity while preserving anti-tumor efficacy in gastric cancer models.

PURPOSE: Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC. METHODS: Eligible patients had metastatic PDAC and at least one, but no more than two prior lines of systemic therapy. A safety lead-in evaluating the combination was conducted and the maximum tolerated dose level of LY3214996 was identified. Patients were then randomly assigned in a 1:1 fashion to receive either LY3214996 200 mg orally (PO) once daily + HCQ 600 mg PO twice a day (arm 1) or LY3214996 400 mg PO once daily (arm 2). The primary end point for this study was disease control rate (DCR). Secondary end points included overall survival (OS) and progression-free survival (PFS). RESULTS: Thirty-nine patients enrolled (20 in arm 1, 19 in arm 2). The DCR rates were 5% in arm 1 and 5.3% in arm 2. The median OS was 2.4 months in arm 1 (95% CI, 1.3 to 5.8) and 4.6 months in arm 2 (95% CI, 3.1 to 5.7). The median PFS was 1.3 months in arm 1 (95% CI, 0.8 to 1.8) and 1.9 months in arm 2 (95% CI, 1.644 to 2.4). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase, anorexia, and cytopenias. Exploratory analysis using patient-derived PDAC organoids did not show evidence of synergistic antiproliferative activity of LY3214996 in combination with chloroquine. CONCLUSION: LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC.

Are the transmembrane mucins, MUC1, MUC4 and MUC16, differentially expressed in endometriosis compared with normal endometrium?

<p>Supplemental Table 7A: Clinical evaluation and characterisitcs of KPC mice treated until clinical endpoint. Supplemental Table 7B: Clinical evaluation and characterisitcs of KPC mice treated for 3 days.</p>