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.

Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines

“…Often multidrug resistance arises upon initial response [6, 7], emphasizing the need for new therapeutic drugs to improve treatment efficiency in RMS [8]. …”

A novel case of an aggressive superficial spindle cell sarcoma in an adult resembling fibrosarcomatous dermatofibrosarcoma protuberans and harboring an EML4‐NTRK3 fusion

“…Raw sequencing data were converted to FASTQ files using Illumina's bcl2fastq software (v2.20.0.422). FASTQs files were used as input to STAR‐Fusion version 1.2.0 to identify putative fusion transcripts. Candidate fusions were filtered with FusionInspector (part of the STAR‐Fusion package), using default parameters …”

“…The former category comprises approximately 20% to 30% of sarcomas and many of these translocations involve protein kinases that are vital in regulating cell growth, angiogenesis, apoptosis, and metastasis . These kinase fusions cause oncogenic transformation through the deregulation of their signaling pathways, and although it is increasingly evident that they are not as diagnostically specific as once thought, they can potentially be targeted for therapeutic purposes.…”

Molecular mechanisms for tumour resistance to chemotherapy

“…To overcome tumour chemoresistance, a number of reversing agents have been developed and many of them are under clinical trial. These reversing agents often target key drug metabolizing enzymes or drug transporters, drug targets or key signalling transduction molecules, or apoptosis . Some highly selective and potent inhibitors or small‐interfering RNAs have shown great potential in enhancing the chemosenstivity especially when combined with cytotoxic drugs.…”