Abstract C083: Profiling of PDK1 inhibitor SNS-510 shows potent activity in hematologic and solid tumor cancer models and identifies CDKN2A-mutated cancers as potential targets with enhanced sensitivity

Abstract

Abstract Background: Phosphatidylinositol (PI) dependent kinase 1, PDK1, is a master kinase that activates kinases important in cell growth and survival including members of the AKT, PKC, RSK and SGK families. PDK1 can interact with its substrates through PI-dependent or PI-independent (PIF-mediated) mechanisms. SNS-510 is a potent inhibitor of active and inactive conformations of PDK1 and binds deep in the adaptive pocket. This interaction perturbs the PIF-pocket, thereby affecting both PI-dependent and -independent substrates (Hansen Mol Cancer Ther 2015). SNS-510 is also a potent FLT3 inhibitor. Methods and Results: SNS-510 activity was evaluated in 320 OncoPanel™ cell lines derived from 20 different cancer types and exposed for 72 hours to a range of drug concentrations (10 µM-1 nM). SNS-510 showed strong and consistent anti-proliferative activity (overall median IC50 537 nM; range 14 nM-10 µM). Cell lines with IC50 <250 nM were classified as sensitive to SNS-510, while those with IC50 >2 μM were classified as resistant. Among the 59 cell lines classified as sensitive, the most prevalent tumor origin was lymphoma followed by leukemia, kidney and lung cancer. The AML FLT3-ITD positive cell line MV4-11 was the most sensitive cell line across the entire OncoPanel™ (IC50 14 nM). Univariate analysis comparing drug response data and public genomics data for the OncoPanel™ cell lines revealed potential biomarkers associated with sensitivity and resistance to SNS-510. The presence of mutations or deletions in the CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) gene was the genomic feature most significantly associated with sensitivity to SNS-510 (p=4.2E-05). Deletions in C9orf53 (CDKN2A divergent transcript), CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) and CDKN2BAS (CDKN2B Antisense RNA 1) genes were also associated with significant sensitivity to SNS-510. Twenty-six (44%) sensitive cell lines were carriers of a CDKN2A mutation or deletion while only 7 (12%) resistant cell lines had a genetic defect in CDKN2A. We previously demonstrated (Hansen Mol Cancer Ther 2015) PDK1/RSK2/P70S6K/AKT pathway modulation and sustained antitumor effects in a human AML MV4-11 FLT3-ITD xenograft mouse model after SNS-510 administration PO. We have now evaluated SNS-510 antitumor activity in a human AML MOLM-16 FLT3 wild-type xenograft mouse model. Potent and dose-dependent tumor growth inhibition (range 52-97%) was observed in the MOLM16 model at SNS-510 PO dose levels of 10, 25 and 50 mg/kg qdx21. The antitumor efficacy was correlated with a profound drug-induced decrease in phospho-PDK1 (Ser241), phospho-AKT (Thr308) and phospho-RSK2 (Ser227) in MOLM16 tumor lysates. Conclusion: SNS-510 is a potent, orally bioavailable PDK1 inhibitor with broad activity in both hematologic and solid tumor cancers. SNS-510 inhibition of PDK1-signaling correlates with antitumor activity at tolerated doses and schedules in both FLT3-ITD and FLT3 wild-type AML xenograft mouse models. Profiling (anti-proliferative and molecular) in the OncoPanel cancer cell line screen identified CDKN2A mutated tumors as particularly sensitive to SNS-510, supporting a potential role by PDK1 inhibitors in combination with CDK4/6 inhibitors to reverse resistance and improve activity (Jansen Cancer Res 2017). Citation Format: Pietro Taverna, Stig Hansen, Jeff Iwig, Gene Jamieson, Judy A Fox. Profiling of PDK1 inhibitor SNS-510 shows potent activity in hematologic and solid tumor cancer models and identifies CDKN2A-mutated cancers as potential targets with enhanced sensitivity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C083. doi:10.1158/1535-7163.TARG-19-C083