Biology subjects

Rix, U.

Publications and source records attributed to Rix, U..

4 recordsLinked to original sources

bioRxiv2025

Dual targeting of RET and SRC synergizes in RET fusion-positive cancer cells

RET fusions drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite new selective RET tyrosine kinase inhibitors (TKIs) resistance usually occurs and is often driven by RET-independent bypass mechanisms. Previous studies have implied crosstalk between RET and SRC, but the anti-cancer effects of targeting SRC combined with selective RET TKIs and the underlying molecular mechanisms are not fully understood. Our results showed that the multitargeted SRC TKI dasatinib significantly enhanced efficacy of RET TKIs in RET fusion-positive (RET+) NSCLC and PTC cells. Genetic rescue experiments validated that the combination effects between RET TKIs and dasatinib were indeed SRC-dependent. Phosphoproteomics analysis and validation using selective inhibitors and siRNAs determined that synergy was primarily mediated by suppression of downstream PAK signaling, with contributions from AKT and S6. Importantly, synergy was also observed with eCF506 (NXP900), a next-generation clinical SRC inhibitor. Finally, both SRC TKIs restored sensitivity in selpercatinib-resistant RET+PTC cells. These results elucidate RET and SRC signaling crosstalk in RET+ NSCLC and PTC suggesting that co-inhibiting SRC has clinical potential in TKI-naive and -resistant RET+ cancers.

cancer biology↗

bioRxiv2024

Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling

Cancer-associated fibroblasts (CAFs) are associated with tumor progression and modulate drug sensitivity of cancer cells. However, the underlying mechanisms are often incompletely understood and crosstalk between tumor cells and CAFs involves soluble secreted as well as adhesion proteins. Interrogating a panel of non-small cell lung cancer (NSCLC) cell lines driven by EML4-ALK fusions, we observed substantial CAF-mediated drug resistance to clinical ALK tyrosine kinase inhibitors (TKIs). Array-based cytokine profiling of fibroblast-derived conditioned- media identified HGF-MET signaling as a major contributor to CAF-mediated paracrine resistance that can be overcome by MET TKIs. However, Cell Type specific labeling using Amino acid Precursors (CTAP)-based expression and phosphoproteomics in direct coculture also highlighted a critical role for the fibronectin-integrin pathway. Flow cytometry analysis confirmed activation of integrin {beta}1 (ITGB1) in lung cancer cells by CAF coculture. Treatment with pharmacological inhibitors, cancer cell-specific silencing or CRISPR-Cas9-mediated knockout of ITGB1 overcame adhesion protein-mediated resistance. Concurrent targeting of MET and integrin signaling effectively abrogated CAF-mediated resistance of EML4-ALK-driven NSCLC cells to ALK TKIs in vitro. Consistently, combination of the ALK TKI alectinib with the MET TKI capmatinib and/or the integrin inhibitor cilengitide was significantly more efficacious than single agent treatment in suppressing tumor growth using an in vivo EML4-ALK-dependent allograft mouse model of NSCLC. In summary, these findings emphasize the complexity of resistance-associated crosstalk between CAFs and cancer cells, which can involve multiple concurrent signaling pathways, and illustrate how comprehensive elucidation of paracrine and juxtacrine resistance mechanisms can inform on more effective therapeutic approaches.

cancer biology↗

bioRxiv2023

The lipid phosphatase activity of PTEN dampens FRA1 expression via AKT/mTOR signaling to suppress melanoma

PTEN, a phosphatase frequently inactivated in melanoma, opposes PI3K/AKT/mTOR pathway activation. However, AKT- and mTOR-targeted therapies have so far yielded insufficient results in preclinical models and clinical trials of melanoma. We therefore examined whether PTEN suppresses melanoma through lipid phosphatase-independent functions or by opposing lipid phosphatase-dependent, AKT-independent pathways. Restoring different PTEN functions in PTEN-deficient cells or mouse models revealed that PTEN lipid phosphatase activity predominantly suppresses melanoma with minimal contribution from its protein phosphatase and scaffold functions. A drug screen highlighted the dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Moreover, activation of AKT was sufficient to overcome several aspects of PTEN-mediated melanoma suppression. Phosphoproteomics analysis of the PTEN lipid phosphatase activity identified the AP-1 transcription factor FRA1 as a downstream effector. PTEN regulates FRA1 translation via AKT/mTOR and FRA1 overexpression overcomes PTEN-mediated melanoma suppression. Our study affirms AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis.

cancer biology↗

bioRxiv2022

Targeting BET Proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML

Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development. We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce resistance to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy and credential this using patient-derived xenografts supporting the clinical investigation of this combination.

cancer biology↗