Cancer, a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body, has developed as second leading cause of disease-related death [
1,
2]. Lots of options served as anti-cancer therapy exist. Among them, chemotherapy applies the most. Indeed, the prescription of chemotherapeutics is such an brilliant success that should be regarded as a milestone in anti-cancer career. However, despite chemotherapeutic outstanding performance treated in cancer, there are accumulating and clear evidences of acquired drug resistance, especially MDR to them [
3,
4], a phenomenon that cancer cells once exposed to one anti-cancer drug show resistance to various other drugs that are structurally and functionally different from the initial anti-cancer drug, impairing drug efficacy and accounting for 90% deaths in cancer. A great deal of researches reveals the potential mechanism conferring MDR in chemotherapy, including kinase domain gene mutation [
5], target gene amplification, the modification of signal pathway and the activation of parallel ones [
6,
7]. Among these, ABC transporter, driven by ATP hydrolysis, plays an essential role in the genesis of MDR, especially ABCB1 [
8], ABCC1 [
9] and ABCG2 [
10]. They’re expressed constitutively in both cancer and normal cells, participating in the process of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) [
11]. ABC transporter has documented as an efflux pump for multiple anti-tumor drugs, which decreases the intracellular drug concentrations and leads to MDR phenotype, implying the modulators of ABC transporter might potentially be applied in MDR cancer cells and act as chemosensitizers, such as verapamil, PSC-833 and GF120918 [
12]. TKIs, also called tyrphostine, a series of pharmaceutical drugs that suppress ATP-binding site of tyrosine kinase, function as a target-specific remedy in anti-cancer regimen [
13]. As far, at least 20 TKIs aiming to various tyrosine kinase, e.g. EGFR, VEGFR, PDGFR [
14], have been generated proven to be effective anti-tumor agents clinically which received the Food and Drug Administration (FDA) approval [
15]. Coincidently, just like tyrosine kinase, ABC transporters happened to have the ATP-binding site. It is conceived that TKIs might be inhibitors of ABC transporters as well as tyrosine kinase. Consequently, an increasing number of testimonies lied on this assumption show numerous TKIs could function as inhibitors of ABC transporter, hence hamper the efflux of anti-cancer drug and promote the intracellular accumulation of them, indicating that TKIs seems to be chemosensitizers in MDR and enhance the efficacy of chemotherapeutic agents by combinational therapy [
16‐
19].
In this present review, we struggle to demonstrate the application of small molecule TKIs and related remedy in the clinical, the relationship between ABC transporter and MDR, as well as the ongoing or accomplished pre-clinical and clinical researches regarding to TKIs’ new-found function as MDR chemosensitizers when combined with conventional chemotherapeutic agent and the underlying mechanism on it. We sincerely hope that the information involved here could serve as references to overcome MDR and diminish unnecessary side effect, ultimately optimize the treatment in anticancer therapy.
Clinical trials about TKIs enhanced conventional chemotherapeutics
In contrast to a large number of in vitro, in vivo and ex-vivo experiments aforementioned, quite a few clinical trials focused on whether TKIs enhance the efficacy of conventional chemotherapy are documented due to the its complexity and side-effect when applied in human, along with only several of them received positive outcomes (Table
4).
Table 4
Clinical trials of co-administration regimen in resistant patients
Erlotinib+Gemcitabine | Pancreatic cancer | |
Lapatinib+Capecitabine | Breast cancer | |
Nintedanib+Docetaxel | NSCLC | |
Erlotinib+Everolimus | Head and Neck squamous cell carcinoma | |
Erlotinib+Carboplatin | Ovarian cancer | |
Erlotinib+Topotecan | Solid tumor | |
Lapatinib+Epirubicin | Breast cancer | NCT 00753207 |
Sorafenib+Paclitaxel | Solid tumor | NCT 00572078 |
Gemcitabine alone became the first-line treatment for pancreatic cancer decades ago. Until now, an increasing number of evidences showed that cancer cells had developed drug resistance to it [
99]. To overcome the resistance, a study conducted by Moore et al. revealed that in pancreatic cancer, overall survival was significantly longer in the erlotinib/gemcitabine arm compared with gemcitabine alone arm with an estimated HR of 0.82 (95%CI: 0.69–0.99,
P = 0.038). Median survival times were 6.24 months versus 5.91 months for the erlotinib/gemcitabine versus placebo/gemcitabine groups with 1-year survival rates of 23% (95%CI: 18%–28%) and 17% (95%CI: 12%–21%), respectively (
P = 0.023), suggesting erlotinib significantly enhanced the efficacy of gemcitabine in pancreatic cancer [
100]. A systematic review with meta-analysis accomplished by Yang et al. concluded that gemcitabine plus erlotinib represent a new option for the treatment of advanced pancreatic cancer, with modest but clinically meaningful compared gemcitabine alone [
101].
In 2007, FDA approved the co-administration of lapatinib and capecitabine in HER-2-overexpressing metastatic breast cancer who had received but failed the prior therapy including anthracycline, taxane and trastuzumab [
102]. In order to evaluating the efficacy of this combination, a phase III study conducted by Geyer et al. showed that lapatinib plus capecitabine improved time to progression (8.4 months) compared with capecitabine alone (4.4 months,
P < 0.001) [
103]. What’s more, a study initiated by Cetin et al. recruited 203 patients who were in the condition of HER2-positive metastatic breast cancer progressing after trastuzumab and chemotherapy including anthracycline and taxane, and treated them with the combination of lapatinib and capecitabine. Among all 203 patients, there were 7 complete responses (CRs), 61 partial responses (PRs) and 77 stable diseases (SDs). The median PFS was 7 months (95%CI: 6–10 months) while median OS was 15 months (95%CI: 12–18 months), indicating lapatinib and capecitabine combination therapy is effective in these patients [
104].
Docetaxel, as we know, is approved to be administrated as a treatment for numerous cancers. Unfortunately it is abundantly reported to develop drug resistance in recent years [
105]. To handle this resistance, a study conducted by Reck et al. found that in this population of patients with adenocarcinoma who had progressed after first-line therapy, median PFS was significantly longer in the docetaxel plus nintedanib group compared docetxel alone, both at the time of the primary PFS analysis (
P = 0.0008) and final overall survival analysis (
P = 0.0005) [
106], identifying the dramatic efficacy of the combination of nintedanib and docetaxel in patients with advanced NSCLC progressing after the failure of first-line chemotherapy.
Despite the several successful combination mentioned above, most trials did not focus on the reversal of ABC transporter-mediated MDR. In the last decade, a huge amount of effort has been invested in the field of ABC drug transporters to identify, develop, and clinically evaluate a variety of agents known to antagonize the function of these transporters as a means of overcoming tumor resistance. The major reasons for the failure of this strategy could be explained in retrospect by multiple factors and variable components that are involved in the development of drug resistance in patients. We advocate further study on combination of TKI (such as afatinib, belongs to 3rd generation MDR modulator) and conventional chemotherapy in clinic in the patients with ABC-transporter expression. Patient selection for clinical studies is a key factor. Patients whose tumors express high levels of ABC-transporter will obviously receive the most benefit from modulators. Therefore, drug-resistance reversal trials should ideally be performed in individuals with tumors that initially are chemosensitive but develop drug resistance following initial therapy, which is marked by an increase in the expression of ABC drug transporter.