45P - Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple Negative Breast Cancer

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Breast Cancer
Presenter Erik Knudsen
Authors E.S. Knudsen1, S. Chung1, A. Witkiewicz2
  • 1Medicine, University of Arizona, 85724 - Tucson/US
  • 2Pathology, University of Arizona, 85724 - Tucson/US

Abstract

Body

PURPOSE: A precision approach to the treatment of triple negative breast cancer (TNBC) has been lacking, and the vast majority of cases are still treated based on cytotoxic chemotherapy. In part, this is due to the genetic complexity of TNBC and tumor suppressor loss as the key driver event in this disease. Here a targeted approach was taken to identify pharmaceutical vulnerabilities imparted by loss of the RB tumor suppressor in TNBC.

BACKGROUND: In the genetic (n=94) and histological (n=220) analysis of TNBC approximately 30% of cases exhibit loss of function of the RB tumor suppressor. This event deregulates cell cycle progression and is associated with the aberrant expression of a number of genes that are known drug targets.

EXPERIMENTAL DESIGN: High-throughput drug screening was employed to delineate cancer drugs that harbor selective activity against the loss of RB in TNBC. Cell lines with both naturally occurring RB loss and CRISP/CAS9 deletions were used to define selectivity. In addition, counter-screening with RB “super-activation” and competitive assays were used to validate findings. Biochemical and xenograft studies elucidated mechanisms of action and efficacy respectively.

RESULTS: RB loss was associated with increased sensitivity to select chemotherapies and drugs targeting DNA-damage checkpoints (e.g. CHK1), and chromosome segregation (e.g. PLK1). These data agree with the function of RB in controlling cell cycle regulatory processes, and are consistent with analysis of of clinical specimens indicating a role for RB in the response to neoadjuvant chemotherapy. We delineated combination treatments that were particularly active in RB-deficient TNBC xenograft models and yielded durable disease control. Optimized immunohistochemical staining and molecular approaches are in place to prospectively identify tumors that have lost RB function.

CONCLUSION: Together, these findings serve as the basis for a targeted approach to treatment of a substantial fraction of TNBC cases based on loss of this critical tumor suppressor.

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