Initial AXL and MCL-1 inhibition contributes to abolishing lazertinib tolerance in EGFR-mutant lung cancer cells.

Lazertinib, a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrates marked efficacy in EGFR-mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells.

Nationwide data from comprehensive genomic profiling assays for detecting driver oncogenes in non-small cell lung cancer.

Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment.

Prospective Observational Study of Ramucirumab Plus Docetaxel After Combined Chemoimmunotherapy in Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. PATIENTS AND METHODS: This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. RESULTS: Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. CONCLUSION: Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.

Depth of response and treatment outcomes of immune checkpoint inhibitor-based therapy in patients with advanced non-small cell lung cancer and high PD-L1 expression: An exploratory analysis of retrospective multicenter cohort.

The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 = ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.

High levels of AXL expression in untreated EGFR-mutated non-small cell lung cancer negatively impacts the use of osimertinib.

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.

Predictive value of p53 and AXL immunostaining for the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor-mutant non-small cell lung cancer.

BACKGROUND: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. METHODS: We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. RESULTS: A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). CONCLUSION: The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted.

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia. METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples. RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43). CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease.

We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC50 of 5.12nM.

Essentiality of tetramer formation of Cellulomonas parahominis L-ribose isomerase involved in novel L-ribose metabolic pathway.

L-Ribose isomerase from Cellulomonas parahominis MB426 (CpL-RI) can catalyze the isomerization between L-ribose and L-ribulose, which are non-abundant in nature and called rare sugars. CpL-RI has a broad substrate specificity and can catalyze the isomerization between D-lyxose and D-xylulose, D-talose and D-tagatose, L-allose and L-psicose, L-gulose and L-sorbose, and D-mannose and D-fructose. To elucidate the molecular basis underlying the substrate recognition mechanism of CpL-RI, the crystal structures of CpL-RI alone and in complexes with L-ribose, L-allose, and L-psicose were determined. The structure of CpL-RI was very similar to that of L-ribose isomerase from Acinetobacter sp. strain DL-28, previously determined by us. CpL-RI had a cupin-type ß-barrel structure, and the catalytic site was detected between two large ß-sheets with a bound metal ion. The bound substrates coordinated to the metal ion, and Glu113 and Glu204 were shown to act as acid/base catalysts in the catalytic reaction via a cis-enediol intermediate. Glu211 and Arg243 were found to be responsible for the recognition of substrates with various configurations at 4- and 5-positions of sugar. CpL-RI formed a homo-tetramer in crystals, and the catalytic site independently consisted of residues within a subunit, suggesting that the catalytic site acted independently. Crystal structure and site-direct mutagenesis analyses showed that the tetramer structure is essential for the enzyme activity and that each subunit of CpL-RI could be structurally stabilized by intermolecular contacts with other subunits. The results of growth complementation assays suggest that CpL-RI is involved in a novel metabolic pathway using L-ribose as a carbon source.

Production of L-allose and D-talose from L-psicose and D-tagatose by L-ribose isomerase.

L-ribose isomerase (L-RI) from Cellulomonas parahominis MB426 can convert L-psicose and D-tagatose to L-allose and D-talose, respectively. Partially purified recombinant L-RI from Escherichia coli JM109 was immobilized on DIAION HPA25L resin and then utilized to produce L-allose and D-talose. Conversion reaction was performed with the reaction mixture containing 10% L-psicose or D-tagatose and immobilized L-RI at 40 °C. At equilibrium state, the yield of L-allose and D-talose was 35.0% and 13.0%, respectively. Immobilized enzyme could convert L-psicose to L-allose without remarkable decrease in the enzyme activity over 7 times use and D-tagatose to D-talose over 37 times use. After separation and concentration, the mixture solution of L-allose and D-talose was concentrated up to 70% and crystallized by keeping at 4 °C. L-Allose and d-talose crystals were collected from the syrup by filtration. The final yield was 23.0% L-allose and 7.30% D-talose that were obtained from L-psicose and D-tagatose, respectively.

Enzymatic production of three 6-deoxy-aldohexoses from L-rhamnose.

6-Deoxy-L-glucose, 6-deoxy-L-altrose, and 6-deoxy-L-allose were produced from L-rhamnose with an immobilized enzyme that was partially purified (IE) and an immobilized Escherichia coli recombinant treated with toluene (TT). 6-Deoxy-L-psicose was produced from L-rhamnose by a combination of L-rhamnose isomerase (TT-PsLRhI) and D-tagatose 3-epimerase (TT-PcDTE). The purified 6-deoxy-L-psicose was isomerized to 6-deoxy-L-altrose and 6-deoxy-L-allose with L-arabinose isomerase (TT-EaLAI) and L-ribose isomerase (TT-AcLRI), respectively, and then was epimerized to L-rhamnulose with immobilized D-tagatose 3-epimerase (IE-PcDTE). Following purification, L-rhamnulose was converted to 6-deoxy-L-glucose with D-arabinose isomerase (TT-BpDAI). The equilibrium ratios of 6-deoxy-L-psicose:6-deoxy-L-altrose, 6-deoxy-L-psicose:6-deoxy-L-allose, and L-rhamnulose:6-deoxy-L-glucose were 60:40, 40:60, and 27:73, respectively. The production yields of 6-deoxy-L-glucose, 6-deoxy-L-altrose, and 6-deoxy-L-allose from L-rhamnose were 5.4, 14.6, and 25.1%, respectively. These results indicate that the aldose isomerases used in this study acted on 6-deoxy aldohexoses.

ß-d-Gulose.

The title compound, C6H12O6, a C-3 position epimer of d-galactose, crystallized from an aqueous solution, was confirmed as ß-d-pyran-ose with a (4) C 1 (C1) conformation. In the crystal, O-H⋯O hydrogen bonds between the hy-droxy groups at the C-1 and C-6 positions connect mol-ecules into a tape structure with an R 3 (3)(11) ring motif running along the a-axis direction. The tapes are connected by further O-H⋯O hydrogen bonds, forming a three-dimensional network.

[Gasserian ganglion block for trigeminal neuralgia under dexmedetomidine sedation].

We report a case of successful procedural sedation using dexmedetomidine (DEX) in a 68-year-old woman undergoing left gasserian ganglion block for intractable trigeminal neuralgia. DEX was chosen to provide an effective sedation and clear communication about the injection of drugs or thermocoagulation. After 15 minutes of DEX administration at 0.8 microg x kg(-1) x hr(-1), nerve block needle insertion was bearable. The patient could feel a weakening of the sensation of her left maxilla and mandible after receiving a 0.4 ml mepivacaine test dose. High-frequency thermocoagulation elicited tolerable radiating pain with minimum vital sign change. She was comfortable and had no communication difficulty under DEX sedation. DEX sedation for interventional pain management during procedures such as gasserian ganglion block may be useful.

Cardiopulmonary Management for Severe Aortic Valve Stenosis With Noninvasive Ventilation Using a Nasopharyngeal Tube.

The nasopharyngeal tube (NT) is an effective interface for noninvasive ventilation (NIV). In cases of severe heart failure, assistance with noninvasive positive-pressure ventilation (NPPV) effectively reduces afterload and alleviates respiratory effort. We present the case of a three-day-old male neonate diagnosed with severe aortic valve stenosis (AS). In respiratory management, extubation was delayed due to increased respiratory effort and afterload, so this patient was extubated and managed with NPPV using an NT. An uncuffed endotracheal tube was inserted, initiating NIV with a positive end-expiratory pressure of 8 cmH2O. The patient exhibited stable vital signs post-extubation and was weaned off NPPV and transferred to the general ward. In this case of severe AS, the use of NT as an interface for NPPV demonstrated efficacy in respiratory and circulatory management. This approach could have shortened the duration of mechanical ventilation and facilitated safe postoperative care, highlighting the potential benefits of NT in managing severe heart failure.

Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells.

Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell-cycle checkpoint inhibitors have attracted attention because they disrupt cell-cycle regulation. Here, we aimed to establish a novel combinational therapeutic strategy to inhibit the cell-cycle checkpoint kinase, ATR in PM cells. The siRNA screening assay showed that anexelekto (AXL) knockdown enhanced cell growth inhibition when exposed to ATR inhibitors, demonstrating the synergistic effects of the ATR and AXL combination in some PM cells. The AXL and ATR inhibitor combination increased cell apoptosis via the Bim protein and suppressed cell migration when compared with each monotherapy. The combined therapeutic targeting of AXL and ATR significantly delayed regrowth compared with monotherapy. Thus, optimal AXL and ATR inhibition may potentially improve the PM outcome.

Clinical significance of chronic pulmonary aspergillosis in lung cancer patients undergoing anticancer drug therapy.

BACKGROUND: Advances in anticancer drugs for lung cancer (LC) have improved the prognosis of LC. Chronic pulmonary aspergillosis (CPA) is a progressive and often exacerbating respiratory disease with a poor prognosis. To date, the prognosis of LC complicated by CPA has not been elucidated. This study investigated the clinical implications of concomitant CPA in patients with LC undergoing anticancer drug treatment. METHODS: Between January 2010 and May 2020, we consecutively enrolled patients with LC complicated with CPA at five different institutions in Japan. We analyzed patients with LC complicated by CPA who received anticancer drug treatment. RESULTS: A total of 10 patients with LC complicated by CPA received anticancer drug treatment. The median overall survival (OS) was 14.57 months (95% confidence interval [CI]: 5.37-21.67). The cause of death in all patients was LC. Six of the seven patients with LC did not show worsening pulmonary aspergillosis lesions during the anticancer drug treatment. Although two patients discontinued anticancer drug treatment due to pneumonitis, CPA complications did not interfere with the continuation of anticancer drug treatment. In univariate analyses, squamous histology (p = 0.01) and body mass index (<18.5 kg/m2) (p = 0.0008) were significantly associated with poorer OS. CONCLUSIONS: This study demonstrated that the cause of death in LC patients with concomitant CPA who received anticancer drug treatments and effective antifungal treatment was LC progression. Further large-scale studies are needed to identify the effect of CPA in patients with LC.

Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer.

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

Efficacy and Safety of Docetaxel plus Ramucirumab for Patients with Pretreated Advanced or Recurrent Non-small Cell Lung Cancer: Focus on Older Patients.

BACKGROUND: Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients. OBJECTIVE: This multicenter retrospective study aimed to investigate the efficacy and safety of second-line treatment regimens in older patients with advanced or recurrent non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively analyzed 145 patients aged ≥ 70 years with advanced or recurrent NSCLC treated with second-line chemotherapy after platinum-based therapy between April 1, 2016, and March 31, 2021. Patients were subdivided into the DTX + RAM (n = 38) and single-agent (n = 107) groups. RESULTS: The median time to treatment failure was 6.3 months (95% confidence interval [CI] 3.6-9.6) in the DTX + RAM group and 2.3 months (95% CI 1.7-3.0) in the single-agent group (p < 0.01). The median overall survival was 15.9 months (95% CI 12.3-Not Achieved) in the DTX + RAM group and 9.4 months (95% CI 6.9-15.1) in the single-agent group (p = 0.01). Grade ≥ 3 adverse events frequency was not significantly different between the two groups, except for edema. Patients in the DTX + RAM group who did not discontinue treatment owing to adverse events exhibited the most favorable prognosis. CONCLUSIONS: These findings suggest that the DTX + RAM combination is an effective second-line therapy for older patients with advanced or recurrent NSCLC, offering favorable efficacy without treatment discontinuation owing to adverse events.

Comparing Three Different Anti-Programmed Death-Ligand 1 Antibodies in Immunohistochemical Evaluation of Combined Chemoimmunotherapy Response in Patients With NSCLC: A Prospective Study.

Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1-predictive markers for response to various immune checkpoint inhibitors in NSCLC-have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.

AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells.

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.