Targeting KRAS in cancer

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 969 - 983

Published: April 1, 2024

Language: Английский

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Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

Nature, Journal Year: 2024, Volume and Issue: 629(8013), P. 927 - 936

Published: April 8, 2024

Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by mutations 1,2 . RMC-7977 is highly selective inhibitor active GTP-bound forms KRAS, HRAS and NRAS, affinity for both mutant wild-type variants 3 More than 90% cases pancreatic ductal adenocarcinoma (PDAC) activating in KRAS 4 Here we assessed therapeutic comprehensive range PDAC models. We observed broad pronounced anti-tumour activity across models following direct at exposures that were well-tolerated vivo. Pharmacological analyses revealed divergent responses tumour versus normal tissues. Treated exhibited waves apoptosis along sustained proliferative arrest, whereas tissues underwent only transient decreases proliferation, no evidence apoptosis. In autochthonous KPC mouse model, treatment resulted profound extension survival followed on-treatment relapse. Analysis relapsed identified Myc copy number gain as prevalent candidate resistance mechanism, which could be overcome combinatorial TEAD vitro. Together, these data establish strong preclinical rationale use broad-spectrum RAS-GTP setting identify promising combination regimen monotherapy resistance.

Language: Английский

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Exploiting the therapeutic implications of KRAS inhibition on tumor immunity

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 338 - 357

Published: March 1, 2024

SummaryOver the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite initial benefit KRAS-G12C inhibitors for patients tumors harboring this mutation, rapid emergence drug resistance underscores urgent need synergize these other therapeutic approaches improve outcomes. mutant tumor cells can create an immunosuppressive microenvironment (TME), suggesting increased susceptibility immunotherapies following inhibition. This provides a rationale combining inhibitory drugs immune checkpoint blockade (ICB). However, achieving synergy clinical setting has proven challenging. Here, we explore how understanding impact on TME guide innovative inhibition immunotherapies, review progress both pre-clinical and stages, discuss challenges future directions.

Language: Английский

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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(11), P. 2135 - 2161

Published: July 5, 2024

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

Language: Английский

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Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: Feb. 3, 2024

Abstract The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study 803 patients with PDAC (42% metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that status and subtypes were prognostic ( p < 0.001). Relative wildtype tumors (median OS 38 months), G12R had similar 34 while Q61 G12D mutated shorter 20 months [HR: 1.9, 95% CI 1.2–3.0, = 0.006] 22 1.7, 1.3–2.3, 0.001], respectively). There was enrichment (34% vs 24%, OR: 1.2–2.4, 0.001) well moderately differentiated (14% 9%, 1.05–2.99, 0.04). Similar findings observed the external validation cohort (PanCAN’s Know Your Tumor® dataset, n 408).

Language: Английский

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Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(6), P. 982 - 993

Published: April 8, 2024

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients previously treated unresectable or metastatic cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four With a median follow-up 11.9 months, ORR 34.0%, disease control 85.1%, and duration 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival 6.9 CI, 5.7-7.4) overall 15.9 11.8-18.8). Treatment-related adverse events (TRAEs) occurred all patients; grade 3-4 27.7% no 5. No TRAEs led to discontinuation. Exploratory analyses suggest circulating tumor DNA identify features acquired resistance.

Language: Английский

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The evolving landscape of tissue‐agnostic therapies in precision oncology

CA A Cancer Journal for Clinicians, Journal Year: 2024, Volume and Issue: 74(5), P. 433 - 452

Published: May 30, 2024

Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero specific genetic anomalies responsible for fueling malignant growth. The watershed moment tumor-agnostic arrived 2017, with US Food and Drug Administration's historic approval pembrolizumab, an immune checkpoint inhibitor. This milestone marked marriage genomics immunology fields, as immunotherapeutic agent gained genomic biomarkers, specifically, microsatellite instability-high mismatch repair deficiency (dMMR). Subsequently, NTRK inhibitors, designed to combat gene fusions prevalent various tumor types, including pediatric cancers adult solid tumors, further underscored potential therapies. Administration approvals targeted (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) pan-cancer efficacy have continued, offering newfound hope patients grappling advanced that harbor particular biomarkers. In this comprehensive review, authors delve into expansive landscape tissue-agnostic targets drugs, shedding light rationale underpinning approach, hurdles it faces, presently approved therapies, voices from patient advocacy perspective, tantalizing prospects horizon. is welcome advance transcends boundaries histology location provide personalized options.

Language: Английский

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Consensus, debate, and prospective on pancreatic cancer treatments

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Oct. 10, 2024

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite improvement multi-modality treatment strategies, prognosis pancreatic was not improved dramatically. For resectable or borderline patients, surgical strategy centered on improving R0 resection rate is consensus; however, role neoadjuvant therapy in patients and optimal chemotherapy with without radiotherapy were debated. Postoperative adjuvant gemcitabine/capecitabine mFOLFIRINOX recommended regardless margin status. Chemotherapy as first-line for advanced metastatic included FOLFIRINOX, gemcitabine/nab-paclitaxel, NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan only standard care second-line therapy. Immunotherapy an innovative although anti-PD-1 antibody currently agent approved by MSI-H, dMMR, TMB-high tumors, which represent very small subset cancers. Combination strategies to increase immunogenicity overcome immunosuppressive tumor microenvironment may sensitize immunotherapy. Targeted therapies represented PARP KRAS inhibitors are also under investigation, showing benefits progression-free survival objective response rate. This review discusses current modalities highlights cancer.

Language: Английский

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Targeting KRAS in pancreatic cancer

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, Journal Year: 2024, Volume and Issue: 32(5), P. 799 - 805

Published: Jan. 1, 2024

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up 90% all pancreatic ductal adenocarcinomas (PDACs) constitutes an attractive target for therapy. However, the most common KRAS mutations PDAC are G12D (44%), G12V (34%) G12R (20%) that not amenable treatment by G12C-directed cysteine-reactive inhibitors such as Sotorasib Adagrasib exhibit clinical efficacy lung cancer. G12C mutant been treated with but this mutation detected only 2%-3% PDAC. Recently, G12D-directed MRTX1133 inhibitor entered trials more development. other may be targeted indirectly via inhibition cognate guanosine exchange factor (GEF) Son Sevenless 1 drives KRAS. These agents seem provide means frequent improve patient outcomes.

Language: Английский

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KRAS G12C inhibitor combination therapies: current evidence and challenge

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: May 2, 2024

Although KRAS G12C inhibitors have proven that is a "druggable" target of cancer, inhibitor monotherapies demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations with other targeted therapies, such as RTK, SHP2, MEK inhibitors, been investigated in trials overcome the resistance. They promising especially by combining EGFR for G12C-mutated colorectal cancer. Many SOS1, ERK, CDK4/6, wild-type RAS, are ongoing. Furthermore, preclinical data suggested additional YAP/TAZ-TEAD FAK farnesyltransferase inhibitors. The immunotherapies chemotherapies also investigated, preliminary results were reported. More recently, KRAS-targeted therapies not being developed, potentially broadening treatment landscape KRAS-mutated cancers. Rationally therapeutics likely play significant role future solid tumors.

Language: Английский

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