Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts

Abstract

PurposeEffective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response.Experimental designWe performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference.ResultsWe identified a number of somatic mutations, mostly shared by the primary tumors and PDX. In particular, BLCAb001, which is less responsive to cisplatin than BLCAb002, carried non-sense mutations in several genes associated with cisplatin resistance, including MLH1, BRCA2, and CASP8. Furthermore, RNA-Seq analysis revealed the overexpression of cisplatin resistance associated genes such as SLC7A11, TLE4, and IL1A in BLCAb001. Two different PIK3CA mutations, E542K and E545K, were identified in BLCAb001 and BLCAb002, respectively. Thus, we tested whether the genomic profiling was predictive of response to a dual PI3K/mTOR targeting agent, LY3023414. Despite harboring similar PIK3CA mutations, BLCAb001 and BLCAb002 exhibited differential response, both in vitro and in vivo. Sustained target modulation was observed in the sensitive model BLCAb002 but not in BLCAb001, as well as decreased autophagy. Interestingly, computational modelling of mutant structures and affinity binding to PI3K revealed that E542K mutation was associated with weaker drug binding than E545K.ConclusionsOur results suggest that the presence of activating PIK3CA mutations may not necessarily predict in vivo treatment response to PI3K targeted therapies, while specific gene alterations may be predictive for cisplatin response in bladder cancer models and, potentially, in patients as well.

In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance

“…A number of small-molecule inhibitors targeting PI3K are currently under different stages of clinical development. Although cell lines harboring PI3KCA mutations are clearly more sensitive to PI3K inhibition than those having wild-type PI3KCA, there are differences in sensitivity based on the specific PI3KCA mutations (20,21). Unfortunately, targeting PI3K with the PI3K-a-specific inhibitor BYL719 failed to induce significant apoptosis even at a very high concentration in head and neck cancer (22).…”

Mechanism of imipenem resistance in metallo‐β‐lactamases expressing pathogenic bacterial spp. and identification of potential inhibitors: An in silico approach

“…The hammerhead scoring function evaluates the interaction of the protein‐ligand complex through different scores such as dock score (D‐score), crash score, Chem score, gold score (G‐score), polar score, potential mean force score (PMF‐score), and consensus score (C‐score). The C‐score combines all the energy scores (D‐score, Crash score, Chem score, G‐score, Polar score, and PMF‐score) and ranks the complex . The best bound compound was selected based on the least binding energy score as well as the number of hydrogen bond (H‐bond) formations.…”

“…The C-score combines all the energy scores (D-score, Crash score, Chem score, G-score, Polar score, and PMF-score) and ranks the complex. 22,23 The best bound compound was selected based on the least binding energy score as well as the number of hydrogen bond (H-bond) formations. The MD simulation run was conducted for each complex.…”

Patient-Derived Urothelial Cancer Xenograft Models: A Systematic Review and Future Perspectives

“…In addition to histology, groups have also examined the genomic fidelity of UC PDX to their initial tumor. Several studies analyzing various genomic parameters showed that genetic identity is preserved between UC PDXs and their original tumor samples, based on karyotyping [28,[30][31][32], flow cytometric quantification of cellular DNA content [31,33], short tandem repeat (STR) polymorphism assay [20], targeted mutational analysis [13,20,21], array-based comparative genomic hybridization (aCGH) [20,21,34], and next-generation sequencing [11,14,35]. These studies revealed that the genetic profiles of UC PDXs and their original tumors while not perfectly matched, share very high homology.…”

“…Pan et al compared whole exome sequencing data of two UC PDXs and original patient tumors to show that they shared 92-97% of genetic aberrations, including multiple druggable targets [14]. Wei et al also showed that in two cases, the majority (91% and 82%) of all mutations were shared by primary and UC PDX samples [35]. Although both comparisons are limited to a small number of cases, these reports prove that UC PDX retains the genetic identity of the primary tumor as reported in other cancer types [7].…”