Targeting protein kinases to reverse multidrug resistance in sarcoma

Abstract

Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.

Keywords: Multidrug resistance (MDR); Protein kinase; Sarcoma.

Figure 1. Targeting tyrosine kinases reverse MDR in sarcomas

Intracellular signal transduction of tyrosine kinases and potential target sites in sarcomas, including receptor tyrosine kinases, non-receptor tyrosine kinases, ABC transporters, and three major downstream signaling pathways: PI3K/AKT/mTOR, MAPK, and JAK/STAT pathways. Bold represent target tyrosine kinases by small molecule kinase inhibitors and mAb.

Figure 2. Targeting serine/threonine kinases reverse MDR in sarcomas

Intracellular signal transduction of serine/threonine kinases and potential target sites in sarcomas, including serine/threonine kinases, ABC transporters, cell cycle, and two major downstream signaling pathways: PI3K/AKT/mTOR and MAPK pathways. Bold represent target serine/threonine kinases by small molecule kinase inhibitors.