Acquired Resistance to KRAS<sup>G12C</sup> Inhibition in Cancer

Awad, Mark M.; Liu, Shengwu; Rybkin, Igor I.; Arbour, Kathryn C.; Dilly, Julien; Zhu, Viola W.; Johnson, Melissa L.; Heist, Rebecca S.; Patil, Tejas; Riely, Gregory J.; Jacobson, Joseph O.; Yang, Xiaoping; Persky, Nicole S.; Root, David E.; Lowder, Kristen E.; Feng, Hanrong; Zhang, Shannon; Haigis, Kevin M.; Hung, Yin P.; Sholl, Lynette M.; Wolpin, Brian M.; Wiese, Julie; Christiansen, Jason; Lee, Jessica; Schrock, Alexa B.; Lim, Lee P.; Garg, Kavita D.; Li, Mark; Engstrom, Lars D.; Waters, Laura; Lawson, J. David; Olson, Peter; Lito, Piro; Ou, Sai‐Hong Ignatius; Christensen, James G.; Jänne, Pasi A.; Aguirre, Andrew J.

doi:10.1056/nejmoa2105281

Cited by 542 publications

(491 citation statements)

References 24 publications

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“…Furthermore, recent studies have identified secondary mutations in KRAS(G12C) cell lines responsible for acquired resistance to MRTX849 and AMG510 treatment in both clinic-derived tumor samples and in resistance mutagenesis experiments. 11,33,34 KRAS proteins with mutations at Y96 were found to be resistant to inhibition by both MRTX849 and AMG510, and proteins with mutations at H95 were found to be resistant to inhibition by MRTX849. These resistance studies further support interactions around H95 as critical to the binding of SII-P-targeted inhibitors.…”

Section: Discussionmentioning

confidence: 99%

KRAS is vulnerable to reversible switch-II pocket engagement in cells

Vasta

Peacock

Zheng

et al. 2021

Preprint

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Current small molecule inhibitors of KRAS (G12C) bind irreversibly in the switch-II pocket, exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the switch-II pocket is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a novel cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the switch-II pockets of many GTP hydrolysis-deficient KRAS hotspot (G12, G13, Q61) mutants are accessible using non-covalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the switch-II pocket as a privileged drug binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.

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Section: Discussionmentioning

confidence: 99%

KRAS is vulnerable to reversible switch-II pocket engagement in cells

Vasta

Peacock

Zheng

et al. 2021

Preprint

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“…Resistance mechanisms may also occur by means of bypass mechanisms such as 3). 18 Although clinical attempts have been made to target these down-stream sites such as MAPK, therapeutic benefit has been limited, which may be due to alternate RAS dependent pathway activations.…”

Section: Mechanism Of Resistancementioning

confidence: 99%

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Zhang

Nagasaka

2021

LCTT

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Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRAS G12C mutation has proven to be challenging due to the abundance of GTP in the cytoplasm, rapid hydrolysis of GTP, and difficulty designing small molecules to achieve sufficient concentration for KRAS inhibition. Based on promising results in both preclinical and clinical trials, sotorasib, a novel KRAS G12C inhibitor, was given conditional approval by the FDA in May 2021. The Phase I portion of the clinical trial produced 32% confirmed response with 56% of patients with stable disease. About 91.2% of patients who received the highest dose of 960mg daily achieved disease control. The Phase II portion, which used 960mg daily dosing resulted in 37.1% of patients with confirmed response and 80.6% of patients with disease control. Both phase I and phase II had similar progression-free survival, in 6.3 months and 6.8 months, respectively. In both phases, grade 4 adverse events occurred in only one patient. The most common adverse events were elevations in LFTs, which down-trended upon dose reduction and steroid treatment. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, resistance mutations to sotorasib are increasingly common. Many proposals have been made to address this, such as the use of combination therapy for synthetic lethality, which are producing encouraging results. Here, we explore in further detail the development of sotorasib, its efficacy, mechanism of resistance, and strategies to overcome these resistances.

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“…Some of these RTKs can also activate PI3K signaling. Additionally, genetic alterations of RTK-RAS-MAPK signaling genes have been found in patients with clinically acquired resistance to KRAS G12C inhibitors [65,66]. While the analysis of re-biopsied tissue samples or circulating tumor DNA (ctDNA) obtained at the time of acquiring resistance to MRTX849 largely identified secondary mutations in KRAS, multiple genetic alterations relating to the activation of PI3K and MAPK signaling were also observed.…”

Section: Kras Dependency and Response To Kras G12c Inhibitorsmentioning

confidence: 99%

“…While the analysis of re-biopsied tissue samples or circulating tumor DNA (ctDNA) obtained at the time of acquiring resistance to MRTX849 largely identified secondary mutations in KRAS, multiple genetic alterations relating to the activation of PI3K and MAPK signaling were also observed. These include the amplification of the KRAS G12C allele, MET amplification, activating mutations in NRAS, BRAF, MAP2K1, and RET, oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3, and loss-of-function mutations in NF1 and PTEN [65]. Furthermore, single-cell RNA sequencing analysis of KRAS G12C mutant NSCLC cell lines revealed that treatment with the KRAS G12C inhibitor ARS1620 induced gene expression and protein synthesis of KRAS G12C [63].…”

Section: Kras Dependency and Response To Kras G12c Inhibitorsmentioning

confidence: 99%

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Abe

Kimura

Hirade

et al. 2021

Cancers

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Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.

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Acquired Resistance to KRAS^G12C Inhibition in Cancer

Cited by 542 publications

References 24 publications

KRAS is vulnerable to reversible switch-II pocket engagement in cells

KRAS is vulnerable to reversible switch-II pocket engagement in cells

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

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Acquired Resistance to KRASG12C Inhibition in Cancer

Cited by 542 publications

References 24 publications

KRAS is vulnerable to reversible switch-II pocket engagement in cells

KRAS is vulnerable to reversible switch-II pocket engagement in cells

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

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Acquired Resistance to KRAS^G12C Inhibition in Cancer