Efficacy and toxicity of KRASG12C inhibitors in advanced solid tumors: a meta-analysis.

BACKGROUND: The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent. METHODS: Clinical trials evaluating KRASG12C inhibitors for advanced solid tumors were searched from PubMed, Embase, and Cochrane Library online databases up to 31st December 2023. The characteristics of the studies and the results of objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate, and treatment-related adverse events (trAEs) were extracted. RESULTS: Ten studies with 925 heavily pretreated advanced patients harboring KRASG12C mutation were included. For total population, the pooled analysis of ORR was 28.6% (95%CI, 21.2-36.6%), DCR was 85.5% (95%CI, 82.2-88.6%), PFS rate at 6 months (PFS6) was 49.6% (95%CI, 41.4-57.9%), PFS rate at 12 months (PFS12) was 26.7% (95%CI, 19.8-34.1%), OS rates at 6 months (OS6) was 76.2% (95%CI, 68.8-82.9%), OS rates at 12 months (OS12) was 47.8% (95%CI, 38.6-57.0%). The pooled analysis of any grade trAEs was 79.3% (95%CI, 66.2-90.0%) and grade three or more trAEs was 24.4% (95%CI, 16.7-32.9%). The median time to response and DoR results from individual data were 1.39 months (95%CI, 1.37-1.41 months) and 10.54 months (95%CI, 7.72-13.36 months). Sotorasib had significantly lower pooled incidences of any trAEs (OR, 0.07, 95%CI, 0.03-0.14) and grade three or more trAES (OR, 0.34, 95%CI, 0.24-0.49) compared with adagrasib. CONCLUSIONS: KRASG12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors; however, most of the pooled results were heterogeneous. Sotorasib has shown better safety results.

Cost-effectiveness of sotorasib as a second-line treatment for non-small cell lung cancer with KRASG12C mutation in China and the United States.

Purpose: To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRASG12C mutation from the China and United States'social perspective. Materials and Methods: A Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves. Results: This economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%. Conclusion: Sotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.

VT204: A Potential Small Molecule Inhibitor Targeting KRASG12C Mutation for Therapeutic Intervention in Non-Small Cell Lung Cancer.

Objectives: The development of effective treatments for non-small cell lung cancer (NSCLC), particularly targeting the KRASG12C mutation, remains a challenge. In this study, we investigated the therapeutic potential of VT204, a small molecule inhibitor of KRASG12C, in NSCLC. Methods: To achieve the objectives, we conducted a comprehensive set of experimental methods. In vitro experiments involved the investigation of VT204 on proliferation, apoptosis, cell cycle dynamics, migration, invasion, and on the RAF/MEK/ERK signaling pathway in NCI-H358 cells. In addition, in vivo experiments were performed to evaluate the influence of VT204 on tumor growth. Results: We demonstrated that VT204 effectively suppressed cell proliferation in NCI-H358 cells, with significant inhibition observed at a concentration of 8 µM. Colony formation assays further supported the inhibitory effect of VT204 on NCI-H358 cell growth. Moreover, VT204 exhibited notable effects on suppressing migration and invasion capacities of NCI-H358 cells, indicating its potential as a metastasis-inhibiting agent. Mechanistic investigations revealed that VT204 induced apoptosis and G2M-phase cell cycle arrest in NCI-H358 cells. Additionally, VT204 modulated the RAF/MEK/ERK signaling pathway, leading to reduced phosphorylation of ERK. In vivo studies using xenograft models confirmed the inhibitory effect of VT204 on NCI-H358 tumor growth. Conclusion: These findings highlight VT204 as a promising therapeutic candidate for NSCLC targeting the KRASG12C mutation.

Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, ß-unsaturated carbonyl of covalent inhibitors.

Utilizing α,ß-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic addition may proceed through a concerted process to form an enolate intermediate, bypassing the need for a base catalyst. This proposed mechanism differs from previous findings. Following the formation of the enolate intermediate, solvent-assisted tautomerization results in the final product. Our calculations indicate that solvent-assisted tautomerization is the rate-limiting step in the catalytic cycle under biological conditions. On the basis of this reaction mechanism, the calculated kinact/ki for two inhibitors is consistent well with the experimental results. Our findings provide new insights into the reaction mechanism between the cysteine of KRASG12C and the covalent inhibitors and may provide valuable information for designing effective covalent inhibitors targeting KRASG12C and other similar targets.

KRASG12C Inhibitor as a Treatment Option for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer.

Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment.

From bench to bedside: current development and emerging trend of KRAS-targeted therapy.

Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRASG12C mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRASG12C have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRASG12C mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRASG12C covalent inhibitors in other KRASG12C-positive malignancies, novel KRAS inhibitors beyond KRASG12C mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRASG12C mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.

Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

BACKGROUND: KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies. METHODS: By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo. RESULTS: KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance. CONCLUSIONS: Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.

Efficacy and toxicity of drugs targeting KRASG12C mutation in non-small cell lung cancer: a meta-analysis.

OBJECTIVE: To systematically analyze the efficacy and toxicity of drugs targeting KRASG12C mutation in non-small cell lung cancer (NSCLC). METHODS: The candidate studies were identified in PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases up to 1 June 2023. Data on efficacy, prognosis, and adverse events (AEs) were extracted and calculated by meta-analysis. RESULTS: Six eligible prospective studies were included in this meta-analysis, including 563 patients with advanced or metastatic NSCLC. For patients with NSCLC, the objective response rate (ORR) of drugs targeting KRASG12C mutation was 37% (95%CI 31-43), median duration of response (DOR) was 8.89 months (95%CI 7.96-9.83), and median progression-free survival (PFS) was 6.40 months (95%CI 5.86-6.93). The overall incidence of AEs was 88% (95%CI 79-96) and the incidence of grade ≥3 AEs was 44% (95%CI 24-64). The most common AEs were diarrhea, nausea, fatigue, and vomiting. The most common grade ≥3 AEs were Alaninetransaminase (ALT) or Aspartatetransaminase (AST) increased and diarrhea. CONCLUSION: Sotorasib, Adagrasib, and Garsorasib as the drugs of choice for patients with KRASG12C mutation NSCLC, have definite efficacy and acceptable safety, especially for patients with advanced or metastatic disease and within posterior line therapy.

Targeting oncogenic KRAS in non-small cell lung cancer with EGFR aptamer-conjugated multifunctional RNA nanoparticles.

KRAS mutations are one of the most common oncogenic driver mutations in human cancers, including non-small cell lung cancer (NSCLC), and have established roles in cancer pathogenesis and therapeutic resistance. The development of effective inhibitors of mutant KRAS represents a significant challenge. Three-way junction (3WJ)-based multi-functional RNA nanoparticles have the potential to serve as an effective in vivo siRNA delivery platform with the ability to enhance tumor targeting specificity and visualize biodistribution through an imaging moiety. Herein, we assembled novel EGFRapt-3WJ-siKRASG12C mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRASG12C mutation to silence KRASG12C expression in a tumor cell-specific fashion. We found that EGFRapt-3WJ-siKRASG12C nanoparticles potently depleted cellular KRASG12C expression, resulting in attenuation of downstream MAPK pathway signaling, cell proliferation, migration/invasion ability, and sensitized NSCLC cells to chemoradiotherapy. In vivo, these nanoparticles induced tumor growth inhibition in KRASG12C NSCLC tumor xenografts. Together, this study suggests that the 3WJ pRNA-based platform has the potential to suppress mutant KRAS activity for the treatment of KRAS-driven human cancers, and warrants further development for clinical translation.

Development of a simple high-performance liquid chromatography-ultraviolet method for sotorasib quantification in human plasma: Implications for therapeutic drug monitoring.

Sotorasib, an oral small-molecule inhibitor, reportedly exerts promising activity against Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors. However, the currently administered dose may fail to represent the optimal dose based on the therapeutic efficacy. Herein, we developed a simple and sensitive method using high-performance liquid chromatography with ultraviolet (HPLC-UV) to measure the sotorasib concentration in human plasma. The sotorasib calibration curve exhibited linearity across the concentration range of 0.10-20.0 µg/mL (r2 = 0.9999). The coefficients of intra- and inter-day validation ranged between 0.79-9.75% and 3.01-6.13%, respectively. The assay accuracy ranged between -3.14 and 5.18%, with > 98.5% recovery. Subsequently, we applied the developed method to estimate sotorasib concentrations in a patient with KRAS G12C-mutated non-small cell lung cancer. We anticipate that our HPLC-UV method will be valuable for assessing the safety and efficacy of sotorasib in larger patient cohorts.

Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRASG12C-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. PATIENTS AND METHODS: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. RESULTS: One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053). CONCLUSIONS: We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies.

Strategic Insight into the Combination Therapies for Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths worldwide. The 5-year survival rate after curative resection is almost 80%, however, it is still less than satisfactory for metastatic CRC (mCRC). The combination approach including surgery, chemotherapy, molecular targeted therapy, and immunotherapy is a promising strategy due to its synergistic anticancer effect. Moreover, circulating tumor DNA (ctDNA) analysis has been reported to stratify the post-operative risk of recurrence, thus providing clinically valuable information for deciding to conduct adjuvant chemotherapy. Furthermore, multiple new drugs that potentially target undruggable genes, including KRAS, have been developed. In this review, we discuss the current management of patients with mCRC and future perspectives in the light of a combination therapeutic strategy.

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis.

BACKGROUND: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. METHODS: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRASG12D-mutated patients were analysed as control. RESULTS: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). CONCLUSIONS: First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

New Developments in Treating RAS-Mutated Metastatic Colorectal Cancer.

OPINION STATEMENT: One of the great challenges in digestive oncology is choosing the optimal therapy for RAS-mutated metastatic colorectal cancer (mCRC). Even though the RAS genes and accompanying pathway were identified decades ago and extensive knowledge exists on their role in carcinogenesis, it has proven challenging to translate these insights into new therapies and clinical benefit for patients. However, recently, new drugs targeting this pathway (for example, KRASG12C inhibitors) have shown promising results in clinical trials, as monotherapy or in combination regimens. Although resistance remains an important issue, more knowledge on adaptive resistance and feedback loops in the RAS-pathway has led to strategical combination regimens to overcome this problem. In the past year, many encouraging results have been published or presented at conferences. Even though some of the data is still preliminary, these studies may bring practice-changing results and can lead to a clinical benefit for patients over the coming years. Because of these recent developments, the treatment of RAS-mutated mCRC has become a topic of great interest. Therefore, in this review, we will summarize the standard of care and discuss the most important emerging therapies for this patient population.

D-1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity.

D-1553 is a small molecule inhibitor selectively targeting KRASG12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRASG12C mutation were determined by thermal shift assay and KRASG12C -coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRASG12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRASG12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRASG12C mutation. Compared to the KRAS WT and KRASG12D cell lines, D-1553 selectively inhibited cell viability in multiple KRASG12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRASG12C mutation.

TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC.

KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells.