Drug resistance in glioblastoma: are persisters the key to therapy?

Abstract

Glioblastoma (GBM) represents the main form of brain tumors in adults, and one of the most aggressive cancers overall. The treatment of GBM is a combination of surgery (when possible), chemotherapy (usually Temozolomide, TMZ) and radiotherapy (RT). However, despite this heavy treatment, GBM invariably recur and the median length of survival following diagnosis is 12 to 15 months, with less than 10% of people surviving longer than five years. GBM is extremely resistant to most treatments because of its heterogeneous nature, which is associated with extreme clonal plasticity and the presence of cancer stem cells, refractory to TMZ-and RT-induced cell death. In this review, we explore the mechanisms by which cancer cells, and especially GBM, can acquire resistance to treatment. We describe and discuss the concept of persister/tolerant cells that precede and/or accompany the acquisition of resistance. Persister/tolerant cells are cancer cells that are not eliminated by treatment(s) because of different mechanisms ranging from dormancy/quiescence to senescence. We discuss the possibility of targeting these mechanisms in new therapeutic regimen.

Role of Calcium Homeostasis in Modulating EMT in Cancer

“…The most proliferative and aggressive cancer cells possess essential characteristics that enable them to evade immune surveillance [ 48 , 49 , 50 , 51 , 52 ] and become resistant to drug treatment [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. These characteristics also enable proliferative and aggressive cancer cells to undergo EMT.…”

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

“…AMPK is considered a metabolic hub. During tumor progression and response to radio-and chemotherapy, the microenvironment changes, causing cells to reversibly switch between glycolysis and oxidative phosphorylation, depending on the availability of oxygen [47]. AMPK is induced by low oxygen and glucose deprivation conditions [48].…”

Long Non-Coding RNAs in Multidrug Resistance of Glioblastoma

“…Despite the huge efforts in understanding the underlying mechanisms in the initiation/progression of glioblastoma, its etiology is not fully understood. It is well known that there is a great degree of heterogeneity in different features of glioblastoma such as molecular, cellular, and histological characteristics [ 7 ]. Due to this heterogeneity, the tumor recurrence and development of multidrug resistance (MDR) to conventional chemotherapeutics are two common events in patients with glioblastoma [ 7 ].…”

“…It is well known that there is a great degree of heterogeneity in different features of glioblastoma such as molecular, cellular, and histological characteristics [ 7 ]. Due to this heterogeneity, the tumor recurrence and development of multidrug resistance (MDR) to conventional chemotherapeutics are two common events in patients with glioblastoma [ 7 ]. MDR is defined as the capability of cancer cells to remain resistant against a broad spectrum of anti-cancer treatments [ 8 ].…”