Drug Resistance and the Role of Combination Chemotherapy in Improving Patient Outcomes

Abstract

Resistance to cancer chemotherapy is a common phenomenon especially in metastatic breast cancer (MBC), a setting in which patients typically have had exposure to multiple lines of prior therapy. The subsequent development of drug resistance can result in rapid disease progression during or shortly after completion of treatment. Moreover, cross-class multidrug resistance limits patient treatment choices, particularly in a setting where treatments options are few. One attempt to minimize the impact of drug resistance has been the concurrent use of two or more chemotherapy agents with unrelated mechanisms of action and differing modes of drug resistance, with the intent of blocking the development of multiple intracellular escape pathways essential for tumor survival. Within the past decade, an array of mechanistically diverse agents has augmented the list of combination regimens that may be both synergistic and efficacious in pretreated MBC. The aim of this paper is to review mechanisms of resistance to common chemotherapy agents and to consider current combination treatment options for heavily pretreated and/or drug-resistant patients with MBC.

Balaglitazone reverses P-glycoprotein-mediated multidrug resistance via upregulation of PTEN in a PPARγ-dependent manner in leukemia cells

“…Combining chemotherapeutics with other agents is a novel treatment strategy for decreasing the lethal side effects. 39 In this study, we showed that a combination of DOX and balaglitazone at non-toxic concentrations caused a significant decrease in the IC 50 values of DOX in a concentrationdependent manner. Therefore, simultaneous treatment with DOX and balaglitazone reduced the DOX therapeutic dose and, more importantly, may relieve DOX-induced side effects without any changes in its efficacy.…”

Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis

“…[10][11][12][13][14] These unique molecular features of TNBCs have precluded the development of FDA-approved targeted therapies against this BC subtype. [15][16][17][18][19][20][21] Moreover, the acquisition of chemoresistance is the main cause of disease recurrence and eventual death of BC patients, [22][23][24][25] particularly those harboring TNBC tumors.…”

Proton pump inhibitors as chemosensitizer: new indication for a well-known medication -Brief review

“…In this context the altered pH gradient across the cell membrane in cancer cells -extracellular acidification and alkalization intracellular -supports several of the above mentioned drug resistance mechanisms resulting for example in enhanced drug efflux (by drug enrichment in acidic vesicles, vesicular transport to the cell membrane and drug discharge in the extra cellular space [3,4] , diminished drug influx (impaired uptake of weakly basic chemotherapeutic drugs) or cell cycles arrest (restricted mTOR complex 1 activation with inhibition of protein synthesis and G0 and G1 cell cycle arrest) [6] .…”

“…The resistance of cancer cells towards several different drugs is called multidrug resistance (MDR) [2] . However, both, innate and/or adaptive resistance, critically limit treatment success and remain a key challenge for clinicians [3] .…”