Biomedical subjects

Hans-Guido Wendel

Publications and source records attributed to Hans-Guido Wendel.

5 recordsLinked to original sources

PubMed2026

Targeting eIF4A-dependent translation in genetically complex sarcoma.

Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.

Humans↗

PubMed2006

Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo.

The phosphatidylinositol-3-OH kinase [PI(3)K] pathway is frequently activated in human cancers and represents a rational target for therapeutic intervention. We have previously shown that enforced expression of Akt, which is a downstream effector of PI(3)K, could promote tumorigenesis and drug resistance in the Emu-myc mouse lymphoma model, and that these tumors were particularly sensitive to inhibition of mammalian target of rapamycin (mTOR) with rapamycin when combined with conventional chemotherapy. We now show that reduced dosage of PTEN, a negative regulator of PI(3)K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model. Nonetheless, loss of even one PTEN allele resulted in lymphomas that were resistant to conventional chemotherapy yet sensitive to rapamycin/chemotherapy combinations. These effects could be recapitulated by using RNA interference to suppress PTEN expression in lymphomas, which were previously established in the absence of PI(3)K lesions. Finally, the introduction of lesions that act downstream of mTOR (eIF4E) or disable apoptosis (Bcl-2 and loss of p53) into PTEN+/- lymphomas promoted resistance to rapamycin/chemotherapy combinations. Thus, whether activation of the PI(3)K pathway confers sensitivity or resistance to therapy depends on the therapy used as well as secondary genetic events. Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic.

Animals↗

PubMed2006

Loss of p53 impedes the antileukemic response to BCR-ABL inhibition.

Targeted cancer therapies exploit the continued dependence of cancer cells on oncogenic mutations. Such agents can have remarkable activity against some cancers, although antitumor responses are often heterogeneous, and resistance remains a clinical problem. To gain insight into factors that influence the action of a prototypical targeted drug, we studied the action of imatinib (STI-571, Gleevec) against murine cells and leukemias expressing BCR-ABL, an imatinib target and the initiating oncogene for human chronic myelogenous leukemia (CML). We show that the tumor suppressor p53 is selectively activated by imatinib in BCR-ABL-expressing cells as a result of BCR-ABL kinase inhibition. Inactivation of p53, which can accompany disease progression in human CML, impedes the response to imatinib in vitro and in vivo without preventing BCR-ABL kinase inhibition. Concordantly, p53 mutations are associated with progression to imatinib resistance in some human CMLs. Our results identify p53 as a determinant of the response to oncogene inhibition and suggest one way in which resistance to targeted therapy can emerge during the course of tumor evolution.

Animals↗

PubMed2004

Reversing drug resistance in vivo.

Apoptotic defects occur in oncogenesis and contribute to drug resistance. We have shown that Bcl-2, Akt, and the translational regulator eIF4E cooperate with Myc during lymphomagenesis and are potent inducers of drug resistance. Interestingly, lymphomas expressing Akt, but not those expressing Bcl-2 are sensitized to chemotherapy-induced apoptosis by the mTOR inhibitor rapamycin, an effect that is countered by eIF4E. These results provide in vivo validation for a strategy to reverse drug resistance in human cancers and highlight the potential role of translational deregulation in oncogenesis and resistance. They also illustrate the importance of tailoring cancer therapy based on tumor genotype.

Animals↗

PubMed2004

Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.

Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

Animals↗