Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

Scaltriti, Maurizio; Elkabets, Moshe; Baselga, José

doi:10.1158/1078-0432.ccr-15-1458

Cited by 105 publications

(99 citation statements)

References 56 publications

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“…Ingenuity Regulator Analysis of AD80 direct and indirect targets nominated the tyrosine kinase AXL for further analysis (Table S2). AXL is a member of the TYRO3, AXL, MER (TAM) family of tyrosine kinases, which are emerging as key mediators of resistance to kinase-targeted therapeutics (Elkabets et al, 2015; Scaltriti et al, 2016). Combining the S6K1 inhibitor LY-2779964 with the AXL/TAM kinase inhibitor BMS-777607 elicited substantial cytotoxicity that was selective for PTEN-deficient cells similar to AD80 (Figure 4b, S4a) (Schroeder et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

et al. 2017

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SUMMARY Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.

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Section: Resultsmentioning

confidence: 99%

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

et al. 2017

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“…For example, AXL expression was shown to be higher in patients with drug-resistant leukemia and AXL was induced by chemotherapy drugs in leukemia cell lines (34) and by cisplatin in non-small cell lung cancer cells (35). Several studies by our group and others have shown the involvement of AXL in causing EMT-associated resistance to targeted therapy such as EGFR inhibitors and PI3K inhibitors (8) (36). In these studies, inhibition of AXL in the mesenchymal cancer cells re-sensitized these cells to either chemotherapy or targeted therapy (8, 9, 16, 36).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies by our group and others have shown the involvement of AXL in causing EMT-associated resistance to targeted therapy such as EGFR inhibitors and PI3K inhibitors (8) (36). In these studies, inhibition of AXL in the mesenchymal cancer cells re-sensitized these cells to either chemotherapy or targeted therapy (8, 9, 16, 36). Further, the relationship between EMT and DNA repair pathways has been recently observed in several systems.…”

Section: Discussionmentioning

confidence: 99%

AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

Balaji

Vijayaraghavan

Diao

et al. 2017

Molecular Cancer Research

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Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non-small cell lung cancers (NSCLCs) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBCs) and head and neck squamous cell carcinomas (HNSCCs) and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiation, and targeted therapy. Since the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway. Downregulation or inhibition of AXL directly reversed the EMT phenotype, led to decreased expression of DNA repair genes and diminished efficiency of homologous recombination (HR) and RAD51 foci formation. As a result, AXL inhibition caused a state of HR-deficiency in the cells, making them sensitive to inhibition of the DNA repair protein, PARP1. AXL inhibition synergized with PARP inhibition, leading to apoptotic cell death. AXL expression also associated positively with markers of DNA repair across TNBC, HNSCC and NSCLC patient cohorts.

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“…In this study, we found that the AXL RNA expression level significantly increased in crizotinib‐resistant HCC78R cells. AXL is thought to play a role in acquired resistance to oncoprotein inhibitors, but its role regarding crizotinib resistance has not yet been reported. We examined the effects of 2 clinically relevant AXL inhibitors in HCC78R cells.…”

Section: Discussionmentioning

confidence: 99%

Combined effect of cabozantinib and gefitinib in crizotinib‐resistant lung tumors harboring ROS1 fusions

et al. 2018

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The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non‐small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2‐ROS1 and ABC‐20 harboring CD74‐ROS1, were used as cell line‐based resistance models. Crizotinib‐resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor‐receptor tyrosine kinase array and RNA sequence analysis by next‐generation sequencing. HCC78R cells showed upregulation of HB‐EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB‐EGF or EGF rendered HCC78 cells or ABC‐20 cells resistant to crizotinib. RNA sequence analysis by next‐generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR‐TKI or anti‐EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR‐TKI were more effective against HCC78R cells than monotherapy with an EGFR‐TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB‐EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR‐TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

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Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

Cited by 105 publications

References 56 publications

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

Combined effect of cabozantinib and gefitinib in crizotinib‐resistant lung tumors harboring ROS1 fusions

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