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11 pages, 2213 KiB

Open AccessArticle

Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas

by Radu Pirlog, Nicolas Piton, Aude Lamy, Florian Guisier, Ioana Berindan-Neagoe, Jean-Christophe Sabourin and Florent Marguet

Cancers 2022, 14(4), 1030; https://doi.org/10.3390/cancers14041030 - 17 Feb 2022

Cited by 8 | Viewed by 2911

Abstract

Lung adenocarcinoma (LUAD) is the major subtype of non-small cell lung cancer, accounting for approximately 60% of cases. Molecular analysis of LUADs showed that the KRAS gene is mutated in up to 30% of cases; such cases were previously considered “undruggable”. The KRAS [...] Read more.

Lung adenocarcinoma (LUAD) is the major subtype of non-small cell lung cancer, accounting for approximately 60% of cases. Molecular analysis of LUADs showed that the KRAS gene is mutated in up to 30% of cases; such cases were previously considered “undruggable”. The KRAS G12C mutation has become a hot topic of research after initial, promising, phase I and II trials with targeted inhibitors. We analyzed the morphological and genomic landscape of 202 KRAS G12C mutated LUADs using next-generation sequencing, and identified a specific subtype of patients that could show an improved response to KRAS G12C inhibitors. The main histological subtype was acinar in 29.7% of cases. Tumor-infiltrating lymphocytes (TILs) were highly or moderately abundant in more than 60% of cases. The immunohistochemical profile showed TTF1 positivity in 78.7% of cases and PD-L1 positivity in 44.1% of cases. The molecular profile showed an association between KRAS G12C and STK11 mutations in 25.2% of cases. This subgroup was associated with a statistically significant lower TTF1 (p = 0.0092) and PD-L1 (p < 0.0001) positivity. This type of combined morphological and molecular analysis can improve our understanding of tumor biology, and help us to identify specific patient subgroups that can achieve the best treatment response. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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24 pages, 7421 KiB

Open AccessArticle

Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors

by Nada Tawfeeq, Yonghao Jin and Nazarius S. Lamango

Cancers 2021, 13(22), 5757; https://doi.org/10.3390/cancers13225757 - 17 Nov 2021

Cited by 4 | Viewed by 1999

Abstract

Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the [...] Read more.

Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC₅₀ values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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23 pages, 5973 KiB

Open AccessArticle

Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

by Fernando C. Baltanás, Cynthia Mucientes-Valdivieso, L. Francisco Lorenzo-Martín, Natalia Fernández-Parejo, Rósula García-Navas, Carmen Segrelles, Nuria Calzada, Rocío Fuentes-Mateos, Jesús M. Paramio, Xosé R. Bustelo and Eugenio Santos

Cancers 2021, 13(9), 2152; https://doi.org/10.3390/cancers13092152 - 29 Apr 2021

Cited by 8 | Viewed by 4393

Abstract

Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse [...] Read more.

Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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Review

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19 pages, 2320 KiB

Open AccessEditor’s ChoiceReview

Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

by Damien Reita, Lucile Pabst, Erwan Pencreach, Eric Guérin, Laurent Dano, Valérie Rimelen, Anne-Claire Voegeli, Laurent Vallat, Céline Mascaux and Michèle Beau-Faller

Cancers 2022, 14(5), 1321; https://doi.org/10.3390/cancers14051321 - 4 Mar 2022

Cited by 46 | Viewed by 10611

Abstract

KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of [...] Read more.

KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of GTPAse activity. KRAS mutations are often with poor response of EGFR targeted therapies. KRAS mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. KRAS p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12–14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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34 pages, 1346 KiB

Open AccessReview

KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

by Elena Vendramini, Riccardo Bomben, Federico Pozzo, Tamara Bittolo, Erika Tissino, Valter Gattei and Antonella Zucchetto

Cancers 2022, 14(3), 666; https://doi.org/10.3390/cancers14030666 - 28 Jan 2022

Cited by 16 | Viewed by 7793

Abstract

KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B [...] Read more.

KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B cell proliferation and survival, proved to be critical for B cell receptor-induced ERK pathway activation. In mature B cell neoplasms, commonly seen in adults, KRAS and RAS-MAPK pathway aberrations occur in a relevant fraction of patients, reaching high recurrence in some specific subtypes like multiple myeloma and hairy cell leukemia. As inhibitors targeting the RAS-MAPK pathway are being developed and improved, it is of outmost importance to precisely identify all subgroups of patients that could potentially benefit from their use. Herein, we review the role of KRAS and RAS-MAPK signaling in malignant hematopoiesis, focusing on mature B cell lymphoproliferative disorders. We discuss KRAS and RAS-MAPK pathway aberrations describing type, incidence, mutual exclusion with other genetic abnormalities, and association with prognosis. We review the current therapeutic strategies applied in mature B cell neoplasms to counteract RAS-MAPK signaling in pre-clinical and clinical studies, including most promising combination therapies. We finally present an overview of genetically engineered mouse models bearing KRAS and RAS-MAPK pathway aberrations in the hematopoietic compartment, which are valuable tools in the understanding of cancer biology and etiology. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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12 pages, 3312 KiB

Open AccessEditor’s ChoiceReview

A Breakthrough Brought about by Targeting KRAS^G12C: Nonconformity Is Punished

by Wenjuan Ning, Zhang Yang, Gregor J. Kocher, Patrick Dorn and Ren-Wang Peng

Cancers 2022, 14(2), 390; https://doi.org/10.3390/cancers14020390 - 13 Jan 2022

Cited by 14 | Viewed by 4167

Abstract

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRAS^G12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which [...] Read more.

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRAS^G12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRAS^G12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRAS^G12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRAS^G12C and discuss the challenges of KRAS^G12C inhibitor therapy, as well as future directions. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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19 pages, 989 KiB

Open AccessReview

Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

by Francesca Jacobs, Massimiliano Cani, Umberto Malapelle, Silvia Novello, Valerio Maria Napoli and Paolo Bironzo

Cancers 2021, 13(24), 6332; https://doi.org/10.3390/cancers13246332 - 16 Dec 2021

Cited by 12 | Viewed by 3830

Abstract

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure [...] Read more.

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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14 pages, 1159 KiB

Open AccessReview

Therapeutic Targets of KRAS in Colorectal Cancer

by Shafia Rahman, Shimon Garrel, Michael Gerber, Radhashree Maitra and Sanjay Goel

Cancers 2021, 13(24), 6233; https://doi.org/10.3390/cancers13246233 - 11 Dec 2021

Cited by 10 | Viewed by 3666

Abstract

Patients with metastatic colorectal cancer have a 5-year overall survival of less than 10%. Approximately 45% of patients with metastatic colorectal cancer harbor KRAS mutations. These mutations not only carry a predictive role for the absence of response to anti-EGFR therapy, but also [...] Read more.

Patients with metastatic colorectal cancer have a 5-year overall survival of less than 10%. Approximately 45% of patients with metastatic colorectal cancer harbor KRAS mutations. These mutations not only carry a predictive role for the absence of response to anti-EGFR therapy, but also have a negative prognostic impact on the overall survival. There is a growing unmet need for a personalized therapy approach for patients with KRAS-mutant colorectal cancer. In this article, we focus on the therapeutic strategies targeting KRAS- mutant CRC, while reviewing and elaborating on the discovery and physiology of KRAS. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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12 pages, 1455 KiB

Open AccessReview

Oncogenic KRAS: Signaling and Drug Resistance

by Hyeon Jin Kim, Han Na Lee, Mi Suk Jeong and Se Bok Jang

Cancers 2021, 13(22), 5599; https://doi.org/10.3390/cancers13225599 - 9 Nov 2021

Cited by 36 | Viewed by 5221

Abstract

RAS proteins play a role in many physiological signals transduction processes, including cell growth, division, and survival. The Ras protein has amino acids 188-189 and functions as GTPase. These proteins are switch molecules that cycle between inactive GDP-bound and active GTP-bound by guanine [...] Read more.

RAS proteins play a role in many physiological signals transduction processes, including cell growth, division, and survival. The Ras protein has amino acids 188-189 and functions as GTPase. These proteins are switch molecules that cycle between inactive GDP-bound and active GTP-bound by guanine nucleotide exchange factors (GEFs). KRAS is one of the Ras superfamily isoforms (N-RAS, H-RAS, and K-RAS) that frequently mutate in cancer. The mutation of KRAS is essentially performing the transformation in humans. Since most RAS proteins belong to GTPase, mutated and GTP-bound active RAS is found in many cancers. Despite KRAS being an important molecule in mostly human cancer, including pancreatic and breast, numerous efforts in years past have persisted in cancer therapy targeting KRAS mutant. This review summarizes the biological characteristics of these proteins and the recent progress in the exploration of KRAS-targeted anticancer, leading to new insight. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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13 pages, 14915 KiB

Open AccessReview

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

by Yuta Adachi, Ryo Kimura, Kentaro Hirade and Hiromichi Ebi

Cancers 2021, 13(20), 5081; https://doi.org/10.3390/cancers13205081 - 11 Oct 2021

Cited by 11 | Viewed by 5293

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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15 pages, 1071 KiB

Open AccessReview

KRAS G12C Mutations in NSCLC: From Target to Resistance

by Alfredo Addeo, Giuseppe Luigi Banna and Alex Friedlaender

Cancers 2021, 13(11), 2541; https://doi.org/10.3390/cancers13112541 - 21 May 2021

Cited by 45 | Viewed by 13947

Abstract

Lung cancer represents the most common form of cancer, accounting for 1.8 million deaths globally in 2020. Over the last decade the treatment for advanced and metastatic non-small cell lung cancer have dramatically improved largely thanks to the emergence of two therapeutic breakthroughs: [...] Read more.

Lung cancer represents the most common form of cancer, accounting for 1.8 million deaths globally in 2020. Over the last decade the treatment for advanced and metastatic non-small cell lung cancer have dramatically improved largely thanks to the emergence of two therapeutic breakthroughs: the discovery of immune checkpoint inhibitors and targeting of oncogenic driver alterations. While these therapies hold great promise, they face the same limitation as other inhibitors: the emergence of resistant mechanisms. One such alteration in non-small cell lung cancer is the Kirsten Rat Sarcoma (KRAS) oncogene. KRAS mutations are the most common oncogenic driver in NSCLC, representing roughly 20–25% of cases. The mutation is almost exclusively detected in adenocarcinoma and is found among smokers 90% of the time. Along with the development of new drugs that have been showing promising activity, resistance mechanisms have begun to be clarified. The aim of this review is to unwrap the biology of KRAS in NSCLC with a specific focus on primary and secondary resistance mechanisms and their possible clinical implications. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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14 pages, 532 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance to KRAS^G12C Inhibitors

by Victoria Dunnett-Kane, Pantelis Nicola, Fiona Blackhall and Colin Lindsay

Cancers 2021, 13(1), 151; https://doi.org/10.3390/cancers13010151 - 5 Jan 2021

Cited by 84 | Viewed by 12652

Abstract

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRAS^G12C inhibitors have reached [...] Read more.

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRAS^G12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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