Mechanisms of Resistance to KRASG12C Inhibitors

Dunnett-Kane, Victoria; Nicola, Pantelis; Blackhall, Fiona; Lindsay, Colin R.

doi:10.3390/cancers13010151

Cited by 101 publications

(91 citation statements)

References 76 publications

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“…In agreement with previous reports [38], KRAS G12C is the most common KRAS variant and is currently targetable with clinically-approved covalently-bound inhibitors [39,40]. While clinical trials with various KRAS G12C inhibitors are in progress, data from patients and mouse models point to heterogeneous responses and therapeutic resistance as emerging issues [41]. Again, preclinical models, such as those described here, combined with clinical data, will be invaluable tools in understanding the mechanistic aspects of these issues but also to better stratify patients and possibly design improved inhibitors and therapeutic schemes.…”

Section: Discussionsupporting

confidence: 89%

Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

Kanaki

Voutsina

Markou

et al. 2021

Cancers

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Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients’ peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice.

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Section: Discussionsupporting

confidence: 89%

Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

Kanaki

Voutsina

Markou

et al. 2021

Cancers

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“…Emerging preclinical and clinical evidence shows that the biggest obstacle to KRAS-G12C inhibitor treatment is the inevitable emergence of drug resistance (Fig. 2) [31]. Although the problem of resistance to therapy is multifaceted, intercellular variability or intratumoral heterogeneity is considered to be the main factor leading to KRAS-G12C inhibitor resistance.…”

Section: Resistance To Kras-g12c Inhibitormentioning

confidence: 99%

The KRAS-G12C inhibitor: activity and resistance

2021

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Although it has long been deemed "undruggable", with the development of drugs specifically binding the KRAS-G12C mutant protein, clinical trials that directly inhibit oncogenic RAS have recently made promising improvements. In particular, the covalent KRAS-G12C inhibitors sotorasib and adagrasib are used to treat patients with advanced non-small cell lung cancer (NSCLC) carrying KRAS-G12C mutations. Unfortunately, the vast majority of patients do not respond to KRAS-G12C inhibitor therapy, mainly due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improving the understanding of drug response in the tumor microenvironment may continue to promote the design, testing, and clinical application of KRAS-G12C inhibitors.

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“…However, therapeutic resistance to K-Ras G12C inhibition has been observed in preclinical tumor models and also in the clinic [ 273 , 274 , 275 ]. The PI3K pathway may be implicated in the resistance to K-Ras G12C inhibitors [ 276 ] as preclinical studies have shown failure to inactivate the PI3K signaling pathway after treatment with G12C inhibitors [ 274 , 277 , 278 ]. Importantly, combination of G12C and PI3K pathway inhibitors was effective in vitro and in vivo on models that are resistant to single-agent G12C inhibitor [ 274 ], or significantly improved antitumor activity of G12C inhibitors [ 277 , 279 ], which could be explained by a concomitant inhibition of p-ERK (due to G12C inhibition) and p-AKT [ 274 , 277 ].…”

Section: Ras–pi3k Interaction In Cancermentioning

confidence: 99%

The Importance of Being PI3K in the RAS Signaling Network

Cuesta

Arévalo-Alameda

Castellano

2021

Genes

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Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.

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Mechanisms of Resistance to KRASG12C Inhibitors

Cited by 101 publications

References 76 publications

Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

The KRAS-G12C inhibitor: activity and resistance

The Importance of Being PI3K in the RAS Signaling Network

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