Several in vivo studies have recently been published. caused by lysosomal sequestration of drugs, effectively trapping tyrosine kinase inhibitors and preventing them from reaching their target. Lysosomal drug sequestration seems to work together with ATP-binding cassette transporters, increasing the capacity of lysosomes to mediate sequestration. Both membrane efflux transporter proteins and lysosomes present potential therapeutic targets that could reverse multidrug resistance and increase drug efficacy in combination therapy. This review explains both mechanisms and discusses a number of proposed strategies to circumvent or reverse tyrosine kinase inhibitor-related multidrug resistance. gene have presented with conflicting CEP-32496 outcomes although there may Rabbit Polyclonal to RPC5 be a role for drug response and adverse effects [27,28,29]. ABCB1 and ABCG2 are expressed in cells of relevant tissues such as intestinal lumen and blood-brain barriers, where they transport compounds back into the blood or lumen, while there have been other studies that showed an upregulated expression of these transporters during treatment [24,28,29]. 2.3. Current Strategies to Overcome Resistance in TKI Based Therapy To bypass drug resistance in the medical center, various approaches have been initiated. Clinical resistance to imatinib in the treatment of CML can be caused by numerous mutations that have been recognized, such as one in the gate-keeper ABL (T3151) [29,30,31,32]. Several drugs including dasatinib and nilotinib have been developed to reverse one of 15 common imatinib resistance-related mutations in the Bcr-Abl fusion protein occurring in 85% of patients [30,32,33,34]. NSCLC resistance to EGFR inhibitors generally occurs either via the T790M de-sensitizing mutation or the so-called oncogene kinase switch, where an alternative tyrosine receptor kinase or pathway becomes the primary oncogenic driver instead of EGFR [35,36]. Resistance can also be reversed by TKIs that either target EGFR made up of the T790 mutation (osimertinib) or by inhibitors for MET (crizotinib) or IGF-1R [37]. Regrettably patients will also develop resistance to osimertinib by mutations in the EGFR active site (C797S) [36,38]. Fourth-generation EGFR inhibitors such as EA1045 are currently being developed to bypass this resistance [36,39]. Another example of resistance to TKI in NSCLC is the development of multiple inhibitors against the ALK-EML fusion protein. These patients are usually being treated with CEP-32496 crizotinib [40]. When patients develop resistance, several alternatives are currently available such as ceritinib, alectinib, brigatinib and lorlatinib (examined in [40,41]). The development of these drugs is a nice example of a rationale design of an inhibitor, since they can bypass several mutations such as the steric hindrance caused by the L1196M mutation. Moreover, in contrast to crizotinib, these drugs cannot only pass the blood-brain barrier, but are not transported out of the brain by P-gp or BCRP, accumulate in the brain and are effective against brain metastases [41,42]. However, the bioavailability of lorlatinib can be affected by inhibition of P-gp [43]. Because of these properties, alectinib is now considered as a first-line therapy for adenocarcinoma NSCLC with the ALK-EML4 fusing protein [44]. A common approach to reverse drug resistance is the use of CEP-32496 combinations. Earlier, we reported a mechanism-based approach to develop combinations for cytotoxic drugs, which led to the clinical use of combinations such as of 5-fluorouracil and leucovorin and of cisplatin with gemcitabine [45]. This involved the application of the combination index [46], which was translated to the in vivo models and the medical center [45]. A similar approach was used to design the combination of erlotinib and crizotinib, in which crizotinib mediated inhibition of the cMet pathway can bypass the resistance to erlotinib [36]. An alternative may be the so-called feedback system control, but this did not yet proceed beyond the in vitro screening phase [47]. 2.4. Hurdles in Overcoming Resistance to TKI Notably, other TKI-related drug resistance mechanisms pose more complicated obstacles. Transporters, especially the Multidrug resistance proteins like ABCB1 and ABCG2, confer drug efflux mediated resistance and is more challenging to circumvent [12]. Among the many compounds that have been developed to block efflux transporters [48], some TKIs themselves also exhibit the ability to reverse resistance in MDR-overexpressing cells and thus can potentially act as sensitizers in combined therapy with other TKIs [49,50,51]. 3. Molecular Changes of Transporter Proteins in Drug Resistance 3.1. General.