HER2 mediates clinical resistance to the KRASG12C inhibitor sotorasib, which is overcome by co-targeting SHP2

Ho, Cassandra; Tüns, Alicia I.; Schildhaus, Hans–Ulrich; Wiesweg, Marcel; Grüner, Barbara M.; Hegedűs, Balázs; Schüler, Martin; Schramm, Alexander; Oeck, Sebastian

doi:10.1016/j.ejca.2021.10.003

Cited by 34 publications

(29 citation statements)

References 18 publications

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“…Viability assays confirmed our prediction that osimertinib would synergize with KRAS inhibitors made using the CANDO platform. As osimertinib has a known ability to target ErbB2, which has been implicated in KRAS inhibitor resistance, it is possible inhibition of ErbB2 is responsible for the synergy between ARS-1620 and osimertinib [11,55]. Although our QPCR data showed the expected decrease of MAPK activation with the combination of osimertinib and BAY-293, we did not see the same trend for osimertinib and ARS-1620.…”

Section: Limitations and Future Directionscontrasting

confidence: 67%

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver Kras Mutations in Non-Small Cell Lung Cancer

Bruggemann

Falls

Mangione

et al. 2022

Preprint

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Pharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on their interactions with large protein libraries. We implemented a comprehensive precision medicine drug discovery pipeline within the CANDO platform to determine which drugs are most likely to be effective against mutant phenotypes of non-small cell lung cancer (NSCLC) based on the supposition that drugs with similar interaction profiles (or signatures) will have similar behavior and therefore show synergistic effects. CANDO predicted that osimertinib, an EGFR inhibitor, is most likely to synergize with four KRAS inhibitors. Validation studies with cellular proliferation assays confirmed that osimertinib in combination with ARS-1620, a KRAS G12C inhibitor, and BAY-293, a pan-KRAS inhibitor, showed a synergistic effect on decreasing cellular proliferation by acting on mutant KRAS. Our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales.

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Section: Limitations and Future Directionscontrasting

confidence: 67%

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver Kras Mutations in Non-Small Cell Lung Cancer

Bruggemann

Falls

Mangione

et al. 2022

Preprint

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“…However, SHP2 inhibition was effective in all cell lines tested as well as in xenograft models. Ho et al 64 identified a patient with KRAS G12C NSCLC with a HER2 copy number gain after KRAS G12C inhibitor treatment. In vitro and in vivo studies on this alteration showed that the MAPK pathway remained activated despite KRAS G12C inhibitor treatment, but when combined with an SHP2 inhibitor, this resistance was overcome.…”

Section: Addressing Resistance With Combination Approaches: Preclinicalmentioning

confidence: 99%

More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C

Lietman

Johnson

McCormick

et al. 2022

American Society of Clinical Oncology Educational Book

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Despite the discovery of RAS oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against RAS has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as EGFR, ALK, and ROS1. The discoveries that (1) malignant RAS oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of KRASG12C in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward KRAS-driven cancers. Although the development of allele-selective KRASG12C inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because KRASG12D and KRASG12V are more prevalent than KRASG12C, there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as “the end of the beginning,” with additional discovery and research innovation needed to address the enormous disease burden imposed by RAS-mutant cancers. Here, we describe the development of KRASG12C inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other RAS-mutant cancers.

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“…39 Images were generated using the program PyMOL (http://www.pymol.org). Coordinates have been deposited in RCSB with PDB accession numbers 8AQ7 (9) and 8AQ5 (16). Crystallographic information for both compounds is provided in Table S1.…”

Section: ■ Associated Contentmentioning

confidence: 99%

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS^G12C for the Treatment of Solid Tumors

et al. 2022

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Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS G12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRAS G12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRAS G12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

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HER2 mediates clinical resistance to the KRASG12C inhibitor sotorasib, which is overcome by co-targeting SHP2

Cited by 34 publications

References 18 publications

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver Kras Mutations in Non-Small Cell Lung Cancer

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver Kras Mutations in Non-Small Cell Lung Cancer

More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS^G12C for the Treatment of Solid Tumors

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HER2 mediates clinical resistance to the KRASG12C inhibitor sotorasib, which is overcome by co-targeting SHP2

Cited by 34 publications

References 18 publications

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver Kras Mutations in Non-Small Cell Lung Cancer

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver Kras Mutations in Non-Small Cell Lung Cancer

More to the RAS Story: KRASG12C Inhibition, Resistance Mechanisms, and Moving Beyond KRASG12C

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors

Contact Info

Product

Resources

About

More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS^G12C for the Treatment of Solid Tumors