In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 4026-4026
Abstract:
Background: Oncogenic mutations occurring in the KRAS component of the RAS/MAPK pathway slow nucleotide cycling between its active (GTP-bound) and inactive (GDP-bound) states, shifting it towards the active state and increasing oncogenic signaling. Among these mutations, the glycine-to-cysteine mutation of amino acid 12 (KRASG12C), found in ~13% of non-small cell lung cancer (NSCLC) and ~4% of colorectal cancer (CRC), can be specifically targeted and irreversibly locked in the inactive state by covalent modification of Cys12. We have previously reported the discovery and preclinical profile of JDQ443, a selective, oral, covalent inhibitor of KRASG12C that binds under the Switch II loop. Here, we report its antiproliferative and antitumor activity against panels of cancer cell lines as well as cell- (CDX) and patient-derived (PDX) tumor xenografts. Methods: JDQ443 antiproliferative activity was assessed by a high-throughput cell viability assay in a large panel of KRASG12C (n=17) and non-G12C (n=233) cell lines. Single-agent antitumor activity was assessed against a panel of KRASG12C CDX models from NSCLC (LU99, H2122, H2030, and HCC44), pancreatic (Mia PaCa-2), and esophageal (KYSE410) cancer cell lines, plus one non-G12C lung line (H441; KRASG12V). JDQ443 in vivo activity against a panel of KRASG12C NSCLC (n=10) and CRC (n=9) PDX models was assessed either as a single agent or in combination with TNO155 (SHP2 inhibitor [i]), trametinib (MEKi), or ribociclib (CDK4/6i). In vivo combination studies with TNO155 were also performed in CDX models (LU99, H2030, HCC44, and KYSE410). Results: In vitro, JDQ443 demonstrated potent antiproliferative activity selectively towards KRASG12C cell lines. Dose-dependent tumor growth inhibition/regression was observed for all KRASG12C CDX models, but not for the H441 KRASG12V model, and was independent of once-daily (QD) or twice-daily (BID) dosing. Single-agent antitumor activity (best average response, duration of reduction in tumor doubling time) was observed across both PDX panels and was improved by all three combination treatments. The JDQ443/TNO155 combination improved single-agent activity across CDX models, with comparable antitumor benefit maintained at QD or BID TNO155 schedules in two of three models (LU99 and KYSE410). Combination with TNO155 allowed a reduced dose of JDQ443 to achieve similar target occupancy and antitumor activity versus JDQ443 alone. Conclusions: JDQ443 demonstrates significant activity against a broad range of KRASG12C solid tumor models, both in vitro and in vivo, that is increased when combined with agents targeting both upstream and downstream components of the RAS signaling pathway. The combination benefit of JDQ443 + TNO155 over JDQ443 alone is maintained at reduced doses for both agents. Citation Format: Andreas Weiss, Hans Voshol, Diana Graus Porta, Carmine Fedele, Dario Sterker, Ruben De Kanter, Rowan Stringer, Toni Widmer, Alice Loo, Daniel A. Guthy, Kim S. Beyer, Nils Ostermann, Catherine LeBlanc, Marc Gerspacher, Andrea Vaupel, Richard Sedrani, Frederic Zecri, Saveur-Michel Maria, Francesco Hofmann, Peter Hammerman, Jeff Engelman, Edwige Lorthiois, Simona Cotesta, Saskia M. Brachmann. JDQ443, a covalent inhibitor of KRASG12C with a novel binding mode, shows broad antitumor activity in KRASG12C preclinical models as a single agent and in combination with inhibitors of SHP2, MEK or CDK4/6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4026.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-4026
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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