Src Inhibition Is Still a Relevant Target in Pancreatic Cancer

Abstract

It is with great interest and anticipation that Dr. Chee and colleagues report their phase II study results of dasatinib in the first-line treatment of patients with metastatic pancreatic cancer (PCa) [1]. The authors should be applauded for successfully conducting an important “window of opportunity” study with high hopes of demonstrating benefit. Unfortunately, the study failed to meet the prespecified primary endpoint of improving overall survival. However, we respectfully disagree with the authors’ conclusion that dasatinib has no clinical activity in metastatic PCa. Although it is true that this agent as monotherapy failed to achieve a meaningful composite outcome of overall survival in the patients treated, there were a number of individuals who had durable and sustained response to relatively brief therapy exposure. Whether due to the biologic agent or inherent in the individual patient’s disease biology, such findings are consistent with the National Cancer Institute’s recently reported goal of identifying exceptional responders to therapies. Such identification of clinical responders allows for the pursuit of deep interrogation of their cancer biology to determine a mechanistic rationale that might be exploited further for the benefit of all patients [2]. Thus, efforts should be made to better understand the outcomes and biologic “-omics” associated with the heterogeneous nature of the disease among individual patients with pancreatic cancer. There are significant preclinical data to support the rationale for Src inhibition as a potentially effective therapeutic target in PCa [3–6]. However, the presumption that a single biologic agent would significantly improve survival in metastatic PCa is inconsistent with prior clinical investigation and preclinical data. It may be more therapeutically effective and scientifically rational to consider Src inhibition in combination with cytotoxic therapies based on the following caveats: (a) Constitutively active Src is associated with increased chemoresistance in pancreatic cancer cells [7–9]. (b) Inhibition of Src reduces tumor expression of thymidylate synthase, the target enzyme of 5-fluorouracil; thus, lowering thymidylate synthase levels is associated with subsequent 5-fluorouracil chemoresistance reversal, resulting in substantially decreased in vivo tumor growth and inhibition of progressive distant metastases [10, 11]. (c) Dasatinib can synergistically inhibit oxaliplatin-induced Src activation, and Src inhibition can also increase oxaliplatin activity both in vitro and in vivo [12]. Therefore, we recommend continued investigations for our patients with PCa by developing rational combination therapies that capitalize on therapeutic Src inhibition. A combination clinical trial of Src inhibition with cytotoxic therapies to explore these hypotheses, with correlative molecular tumor and surrogate tissue analyses, is ongoing with active enrollment (NCI ClinicalTrials.gov #NCT01652976).