Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling

Zhang, Baoyuan; Zhang, Yan; Zhang, Jiangwei; Liu, Ping; Jiao, Bo; Wang, Zaiqi; Ren, Ruibao

doi:10.1002/advs.202100250

Cited by 32 publications

(26 citation statements)

References 64 publications

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“…In addition, the resistant tumor was found to have a significantly reduced adaptive immune cell population. 53 Zhang et al 54 found that focal adhesion kinase activity is induced when KRAS G12C is inhibited and may result in tumor fibrosis as a potential mechanism of acquired drug resistance. Cell lines and patient-derived xenograft models from lung and colon adenocarcinoma samples were identified by Hallin et al 55 as having not only resistance mechanisms in RTKs but also genetic dysregulation of the cell cycle.…”

Section: Pathway Activation Via Rtks Upstream Of Kras and Ras/ Mapk A...mentioning

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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Section: Pathway Activation Via Rtks Upstream Of Kras and Ras/ Mapk A...mentioning

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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“…This combination simultaneously reduces the degree of drug resistance. The synergistic benefit of the combination therapy was consistently observed in different CDX and PDX models of KRAS (G12C) cancers [ 122 ]. Besides, activation of the FAK signaling pathway has an impact on the tumor microenvironment [ 123 , 124 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting KRAS mutant cancers: from druggable therapy to drug resistance

et al. 2022

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Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

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“…Our findings open new opportunities to explore other receptors such as FAK (focal adhesion kinases) that have already been related in KRAS mutant patients. FAK may be surrogate markers of aberrant KRAS signaling found in aggressive phenotype in lung cancer [ 29 ]. A similar effect was observed in the KRAS -mutated adenocarcinoma cell line model (A549-FL), used to examine the metastasis mechanisms that identified epithelial–mesenchymal transition (EMT) markers [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines

Oliveira

Gomes

Silva

et al. 2022

IJMS

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Background: EGFR mutations are present in approximately 15–50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype. Methods: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors’ activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index. Results: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 < 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored. Conclusions: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines.

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Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling

Cited by 32 publications

References 64 publications

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

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

Targeting KRAS mutant cancers: from druggable therapy to drug resistance

Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines

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Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling

Cited by 32 publications

References 64 publications

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

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

Targeting KRAS mutant cancers: from druggable therapy to drug resistance

Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines

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Product

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

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