AXL expression

In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.

In addition, we observed that VGLL1 represses AXL expression and suppresses claudin-low phenotype, and that is caused by the VGLL1 mediated nuclear expulsion of TAZ. Therefore, EGFR and AXL seem to represent two different breast tumor subtypes, and their differential expressions is controlled by VGLL1.

This study demonstrates that combined blockade of MET, AXL and EGFR is a feasible strategy for a subset of EGFR-mutant NSCLC.

The GAS6/AXL pathway contributes to immunotherapy resistance in GC. Targeting this pathway may be a novel therapeutic strategy.

Notably, we found the anti-AXL CAR-NK cells could inhibit the BRAFi-resistant melanoma growth and metastasis in vivo preclinical mouse models. Conclusions Our findings propose that Anti-AXL CAR-NK cell immunotherapy is a promising approach to target BRAF inhibitor drug-resistant and metastatic melanoma.

P1, N=20, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Suspended

This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic. The online version contains supplementary material available at 10.1007/s43188-023-00195-z.

Analysis is ongoing to define spatial intratumoral, intranodal, and geographic intertumoral heterogeneity. Our data provide mechanistic insight to the potential for macrophage-specific and AXL-directed therapy to improve immunotherapeutic response and further exploration of potential as a predictive biomarker is warranted.

Hepatocellular carcinoma (HCC) patients at advanced stages receive immunotherapy or treatment with tyrosine kinase inhibitors (TKIs) such as Sorafenib (Sora) or Lenvatinib in frontline as well as Regorafenib (Rego) or Cabozantinib in second-line...Treatment of Rego-insensitive HCC cells with the pan-ErbB family inhibitor Afatinib rather than with Erlotinib blocking ErbB1 reduced cell viability and clonogenicity...HCC patients treated with Sora in first-line and with Rego in second-line displayed elevated serum levels of bFGF, emphasizing bFGF as a predictive biomarker of TKI treatment. Together, these data suggest that the inhibition of ErbBs is synthetic lethal with Rego in Axl-expressing HCC cells, showing a novel vulnerability of HCC.

Combined radiotherapy with Axl inhibition by treatment with R428 and small interfering RNA lentivirus targeting Axl infection significantly reduced cell viability, colony formation ability, DNA double-stranded break repair, and the invasive and migratory ability of 4T-1/IRR cells...The results of western blotting showed that the critical molecular mechanism involved in the radioresistance of TNBC cells was the PI3K/Akt/mTOR signaling pathway induced by Axl activation. Thus, it is hypothesized that targeted Axl therapy combined with radiotherapy may have significant potential for the treatment of TNBC.

It was found that increased expression of Axl, which is known to increase EMT-mediated metastasis in carcinogenesis, may be an indicator of local spread and poor prognosis in PDAC patients. In this respect, it can be promising as a targeted molecule in PDAC patient's individualized treatments.

Lastly, we evaluated the potential of a microRNA signature that targets Axl. By consolidating existing knowledge and identifying research gaps, this review contributes to a better understanding of Axl's role in MM and sets the stage for future investigations and the development of effective therapeutic interventions.

Conclusions Bem was well tolerated in combinations with Pem or D/T in melanoma, but did not increase responses or survival in the efficacy population nor in biomarker defined subgroups. High FOXP3 count in tumour infiltrating inflammatory cells was a strong predictive marker for response to Pem.

To enroll, patients must have experienced failure of an approved programmed death1/ligand-1(PD-1/L1) treatment, epidermal growth factor receptor (EGFR), or anaplastic lymphoma kinase (ALK) inhibitor (either monotherapy or in combination with another therapy such as ipilimumab). Treatment failure is defined as disease progression on a PD-1/L1, EGFR, or ALK inhibitor, or discontinuation of a PD-1/L1, EGFR, or ALK inhibitor due to an adverse event. Enrollment completion is anticipated in 2023.

Tumor protein-based analysis showed that p53 levels may be a predictive factor for clinical outcomes after ICI-based therapy in patients with EGFR-mutant NSCLC. Furthermore, AXL levels in tumors may be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations are warranted to confirm the effects of the expression of tumor p53 and AXL on clinical outcomes after ICI-based therapy.

The study suggests a potential association between increased AXL protein expression and PD-L1 NSCLC, particularly in tumors with high PD-L1 TPS. This observation may indicate a mechanism of resistance to ICIs that could potentially be addressed by using agents targeting AXL receptors. A tissue screening strategy for AXL expression may be optimized by selecting NSCLC samples with positive PD-L1 expression, particularly those with high PD-L1 TPS.

These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

Moreover, the immunogenic potential of drug-treated VEM-resistant melanoma cells results significantly enhanced, given the increased phagocytosis rate of these cells by dendritic cells, which in turn exhibit also a selective down-modulation of the immune checkpoint TIM-3. Overall, our results provide evidence that combined epigenetic-immune drugs can overcome VEM resistance of primary melanoma cells by oncogenic and immune pathways reprogramming, and pave the way for rapidly exploiting this combination to improve BRAFi-resistant metastatic melanoma treatment, also via reinforcement of immune checkpoint inhibitor therapy.

We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

MTE induces endoplasmic reticulum stress-associated immunogenic cell death in NSCLC cells. The anti-tumor effects of MTE are dependent upon endoplasmic reticulum stress. MTE triggers endoplasmic reticulum stress-associated immunogenic cell death by inhibiting AXL activity. Kaempferol is an active component that inhibits AXL activity in MTE. The present research revealed the role of AXL in regulating endoplasmic reticulum stress and enriched the anti-tumor mechanisms of MTE. Moreover, kaempferol may be considered a novel AXL inhibitor.

P1, N=20, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Apr 2023 --> Oct 2023

Furthermore, using an axillary tumor xenograft mouse model, we observed that OA-loaded GC@Lipo led to a significant reduction in tumor progression, accompanied by concentrated enrichment in hepatocytes. These findings strongly support the clinical translation of ASGPR-targeted liposomes for the treatment of HCC.

Mechanistically, NAT10 exerts its oncogenic effects by promoting mRNA stability of receptor tyrosine kinase AXL in an ac4C-dependent manner leading to increased AXL expression and further promoting PDAC cell proliferation and metastasis. Together, our findings highlight the critical of NAT10 in PDAC progression and reveal a novel epigenetic mechanism by which modified mRNA acetylation promotes PDAC metastasis.

Together, the Elongin BC complex regulates AXL and marks a differentiated melanoma phenotype. Implications: This study identifies the Elongin BC complex as a key regulator of AXL expression and marker of melanoma differentiation.

Background: PARP inhibitors (PARPi) as olaparib (OLA) have become the new standard in maintenance treatment in high grade serous ovarian carcinoma (HGSOC) and triple negative breast cancer (TNBC)... This in vitro study suggest a potential role of AXL in OLA resistance and AXL downregulation migh represent a potential mechanism to overcome resistance to OLA in ovarian and TNBC cell lines.

Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.

Knockdown of Axl by siRNA or the treatment with Axl-specific inhibitor R428 dramatically inhibits the migration and invasion of both IgR3 and WM852 in vitro. These findings suggest that Axl enhances the invasion of melanoma cells.

Most importantly, AVB-500 was highly effective at decreasing tumor dissemination of bile duct tumor cells in the peritoneal cavity. This study strongly supports the idea of using the AXL receptor as a new therapeutic target to treat the growth and progression of biliary cancer.

The antitumor activity induced by pAXL×CD3ε in combination with trabectedin was also investigated...pAXL×CD3ε inhibited the in vivo growth of human sarcoma xenografts, increasing the survival of treated mice. Our data demonstrate the antitumor efficacy of pAXL×CD3ε against sarcoma cells, providing a translational framework for the clinical development of pAXL×CD3ε in the treatment of human sarcomas, aggressive and still-incurable malignancies.

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.

In a syngeneic model of SCLC, the combination of bemcentinib, ceralasertib and an anti-PDL1 antibody induced significant tumor regression. Together, these promising findings demonstrate that AXL inhibition may be an effective strategy to target the RS vulnerability common in SCLC.

Treatment of STK11m NSCLC cell lines with the AXL inhibitor bemcentinib led to a reduction in the STK11-associated DDR signature and increase in inflammatory signatures demonstrating the impact of AXL targeting on tumor cells.Due to the high unmet medical need in individuals harboring a STK11 mutation, the encouraging efficacy in the NCT03184571 clinical trial and the high incidence of AXL protein expression in STK11m tumors, a global, open-label Phase 1b/2a trial to determine the safety, tolerability and anti-tumor activity of bemcentinib with SOC (pembrolizumab, pemetrexed and carboplatin) in 1L advanced/metastatic non-squamous NSCLC patients with STK11 mutations and no actionable mutations is currently enrolling. The Phase 1b part of the study will evaluate the safety and tolerability of bemcentinib regardless of STK11 status, whereas the Phase 2a part will assess the efficacy in NSCLC patients with STK11 mutations.1 Li et al., 2022; Cell Rep Med., PMID: 35492873

In the present study, we investigated spatial tumor heterogeneity using autopsy specimens from EGFR mutated NSCLC patients, showing primary resistance to erlotinib plus ramucirumab. The analysis of patient-derived cell lines, established from left pleural effusion before initiation of the treatment, showed that the combination of EGFR-TKIs and an AXL inhibitor remarkably inhibited cell viability compared with EGFR-TKI monotherapy or combination with ramucirumab. Our observations suggested that tumor AXL expression might play a critical role in progression of spatial tumor heterogeneity and primary resistance to EGFR-TKIs for EGFR mutated NSCLC patients.

Using highly variable genes and pharmacogenomic data for acute myeloid leukemia (AML), we developed a drug sensitivity prediction model for the receptor tyrosine kinase inhibitor sorafenib and achieved more than 80% prediction accuracy...Finally, we show that pharmacological inhibition of tyrosine kinase activity enhances AXL expression, phosphorylation of the PKC-substrate cyclic AMP response element binding (CREB) protein, and displays synergy with AXL and PKC inhibitors. Collectively, our data suggest an involvement of AXL in tyrosine kinase inhibitor resistance and link PKC activation as a possible signaling mediator.

To enroll, patients must have experienced failure of an approved programmed death1/ligand-1(PD-1/L1) treatment, epidermal growth factor receptor (EGFR), or anaplastic lymphoma kinase (ALK) inhibitor (either monotherapy or in combination with another therapy such as ipilimumab). Treatment failure is defined as disease progression on a PD-1/L1, EGFR, or ALK inhibitor, or discontinuation of a PD-1/L1, EGFR, or ALK inhibitor due to an adverse event. Enrollment completion is anticipated in 2023.

Trial Design Study BA3011-001 is an ongoing multi-center, open-label phase I/II first-in-human trial designed to evaluate the safety, tolerability, PK, immunogenicity, and antitumor activity of BA3011 alone and in combination with the PD-1 inhibitor nivolumab in adult and adolescent patients 12 years and older with advanced solid tumors. Enrollment in phase II part 2 is expected to commence in January 2023. Legal entity responsible for the study BioAtla, Inc.