Charles L. Sawyers: Publications

Mechanisms of prostate cancer initiation and progression

Our group has developed and characterized many laboratory models to study prostate cancer initiation and progression. We have established new patient-derived xenograft models and organoid lines as well as genetically engineered mouse (GEM) prostate cancer models for driver oncogenes such as MYC and ERG. Our recent work combines GEM models, primary prostate organoid culture, and single cell analysis technologies to characterize the oncogenicity of ERG, ERF and FOXA1, and to study prostate cancer tumor-host signals during metastasis.

Cancer Genomics

I have co-led several comprehensive genomic landscape studies of castration resistant metastatic prostate cancer and founded AACR Project Genomics Neoplasia Information Exchange (GENIE), on open-access clinical genomic data sharing registry for precision oncology.

Mechanisms of resistance to antiandrogen therapy

Although enzalutamide improves survival of men with metastatic prostate cancer, resistance eventually develops. To date, we have reported four distinct mechanisms of resistance to enzalutamide: mutations in the gene encoding AR, bypass of AR receptor signaling via upregulation of the glucocorticoid receptor, SOX2-dependent lineage plasticity (involving TP53 and RB1), and mesenchymal-derived paracrine signaling via NRG1.

Antiandrogen therapy for prostate cancer

In 2004, we reported that increased expression of the androgen receptor (AR) conferred resistance to existing antiandrogen therapies by converting the cellular response from antagonism to agonism. This observation led us to search for new antiandrogens that could overcome this resistance, resulting in the discovery of enzalutamide with our collaborator, Michael Jung at UCLA. Enzalutamide was approved for treatment of advanced prostate cancer in 2012. We also developed apalutamide, which was approved in 2018 for use in men with castration-resistant prostate cancer who are at risk for metastasis to delay disease progression. Apalutamide inhibits the androgen receptor through a mechanism of action similar to enzalutamide.

PI3-kinase signaling in prostate cancer

The high frequency of PTEN loss in prostate cancer led us to study PI3-kinase signaling. We discovered reciprocal negative feedback between PI3-kinase and androgen receptor signaling in prostate cancers with PTEN loss and, with Neal Rosen, therapeutic strategies with combinations of alpha- and beta-specific inhibitors that delay drug resistance. In addition, we discovered an oncogenic role for the vesicular trafficking protein RAB35 in a screen for novel regulators of PI3-kinase activation.

Kinase inhibitors for chronic myeloid leukemia

Our laboratory approach is rooted in our history of expertise in BCR-ABL kinase signal transduction. As a clinician investigator in chronic myeloid leukemia (CML), I co-led the phase I and phase II clinical trials of imatinib (with Brian Druker and Moshe Talpaz) culminating in its FDA approval in 2001. My laboratory discovered mutations in the BCR-ABL kinase domain as the primary mechanism of resistance to imatinib, and then collaborated with John Kuriyan to show that these mutations impaired drug binding through steric hindrance (in some cases) or through altered conformation of the kinase domain (more commonly). Based on predictions from the “altered conformation” hypothesis, we identified dasatinib as a second generation ABL inhibitor that can overcome nearly all forms of imatinib resistance. I co-led the phase I and phase II clinical trials of dasatinib that resulted in its approval by the FDA in 2006.

View a full listing of Charles L. Sawyers: Publications’ journal articles.