1.1. Conventional Therapies and Resistance in Hematologic Neoplasms
The process of self-renewal of hematopoietic stem cells is essential to homeostasis maintenance. Once this process is disrupted and defects in cell differentiation occur, the malignant transformation and the appearance of hematologic neoplasms can be triggered
[9]. Although these neoplasms may have unclear etiology, genetic alterations as chromosomal rearrangements, point mutations, aneuploidies, deletions, insertions, duplications, and/or amplifications are characteristics of hematologic neoplasms
[10][11][12][13].
Leukemias were first described in 1827, and since then, treatment has changed dramatically. First, studies showed that some cases were treated on single-agent chemotherapy by using nitrogen mustard in Hodgkin’s disease and other lymphomas and chronic leukemias, as well as by administration of the folic acid antagonist aminopterin in acute leukemia patients
[14][15][16][17]. The first leukemia treatment protocol was a combination of radiation, arsenic and thorium-X
[15][16] and, even after some decades, arsenic continued as part of leukemia treatment. A study published later demonstrated the successful effect of arsenic in the treatment of promyelocytic leukemia, once 11 patients presented clinical remission after arsenic administration
[18].
Then, research and development of new classes of antitumoral agents such as antimetabolites, antibiotics, and alkaloids with promising results in pre-clinical and clinical tests were inserted in leukemia treatment protocols, first as single agents and after in combination, with the perspective of prolonging or maintaining disease remission
[19]. For example, the 1950s and 1960s introduced several new drugs to antileukemic chemotherapy as the use of cortisone, chlorambucil, mercaptopurine, cytoxan, vincristine, vinblastin, daunorubicin, and bleomycin to the treatment of leukemias and/or lymphomas
[20][21][22][23][24][25][26], methotrexate and vincristine in childhood acute leukemia
[27][28], L-asparaginase and daunorubicin in acute leukemia therapy
[29][30]. In 1958, methotrexate was administered intrathecally to kill leukemic cells present in the central nervous system
[31] and chlorambucil and cyclophosphamide were later used in the treatment of chronic granulocytic and lymphocytic leukemias, respectively
[32][33].
The combined protocols were introduced at the end of the 1960s, with the administration of cyclophosphamide, mercaptopurine, methotrexate, and vincristine in acute lymphocytic leukemia in children
[34], cyclophosphamide and vinca alkaloids in malignant lymphoma
[35] and cytarabine (AraC) and daunorubicin in acute myeloid leukemia
[36]. With the increase in the number of antileukemic drugs and treatment protocols available, and with the better understanding of hematologic neoplasm development, the survival rate improved expressively among pediatric leukemia patients, as well as in patients with Hodgkin’s disease and the non-Hodgkin’s lymphomas
[15][37][38][39].
However, over time, cases of drug resistance to available chemotherapy were diagnosed among patients with relapsed leukemias. Then, protocols with more intensive chemotherapy and radiotherapy were evaluated, with extensively toxic effects on patients
[19][40][41]. In the 1970s, Don Thomas presents bone marrow transplants as a complement to acute leukemia treatment, with promising results, but with several obstacles related to tissue typing, infection control, immunosuppression, transfusion support and the need to develop more specific drugs that escape from cellular resistance
[15][42][43].
There are several factors related to cancer cell resistance to antitumoral compounds described in the literature. Those can be divided into intrinsic factors that are pre-existent to the treatment, and extrinsic ones that are acquired after starting chemotherapy (
Figure 1). Together, those factors are responsible for treatment failure, cancer recurrences in the clinic and enhanced mortality rates among affected patients
[44][45].
Figure 1. Intrinsic and extrinsic mechanisms of drug resistance in cancer. ① Genetic mutations can lead to alterations in the expression of genes related to cellular resistance and surveillance. ② Heterogenous tumors have subpopulations that may not respond to the available cytotoxic drugs, leading to cancer remission after treatment. ③ Some cellular transporters protect our cells from environmental toxins, as anticancer drugs, and reduce the concentration of their intracellular levels. ④ After treatment, new oncogenes can be activated, leading to enhanced proliferation rate of not responsive cells. ⑤ Mutations in genes that encode drug targets reduce drug efficacy in mutated cell lines. ⑥ Treatment can alter the tumor microenvironment (TME) and lead to cross-talk between sensitive cells and the surrounding cells. The exchange of resistance elements with tumor-associated macrophages (TAMs) and other tumoral cell lines lead to enhanced cell resistance to chemotherapy. Created with BioRender.com, accessed date: 20 August 2021.
Intrinsic resistance is characterized by resistance mechanisms inherent to the patient, once that is not triggered by the administration of chemotherapy drugs
[46]. Factors such as (1) the existence of genetic mutations (mutations, gene amplifications, deletions, chromosomal rearrangements, transposition of the genetic elements, translocations, and alterations in microRNA expression), (2) presence of nonsensitive subpopulation (e.g., cancer stem cells) and (3) activation of mechanisms against xenobiotics (such as anticancer drugs) are responsible for reduced efficacy and treatment failure
[46][47][48].
The acquired or extrinsic resistance occurs when the malignant cell line becomes less responsive to chemotherapy over time, that is, the antitumoral drug loses efficacy. The factors that lead to acquired resistance are grouped into the (4) activation of new proto-oncogenes, (5) mutations and/or alterations in transcription of drug targets, (6) modifications in the tumor microenvironment (TME) after the beginning of treatment
[49][50][51].
In leukemias and lymphomas, some resistance mechanisms are more frequent than others. A study showed that the presence of cancer stem cells subpopulations in leukemia is related to less responsiveness to cytotoxicity chemotherapy, once these cells demonstrated a reduced proliferative rate
[52]. In acute myeloid leukemia (AML), the treatment with the AraC is passive of acquired resistance. AraC is a pro-drug that needs to be phosphorylated to AraC-triphosphate to reach its drug target and reduced expression in metabolic pathways and mutations in AML cell lines leads to decreased levels of active drug, causing drug-resistance to AraC treatment
[53][54].
Increased expression of the mechanism of drug efflux is well known as a cause of leukemia recurrence. Transmembrane transporters from the ATP Binding Cassette (ABC) superfamily ABCB1 (
MDR1), ABCC1, ABCG2 are involved in the acquired resistance in AML, acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)
[55][56][57].
CML is characterized by the presence of the Philadelphia chromosome (Ph+). The translocation between chromosomes 9 and 22 creates a chimeric protein BCR activator of RhoGEF and GTPase-ABL proto-oncogene 1 (BCR-ABL1), which has a tyrosine kinase activity
[58][59]. The targeted therapy with tyrosine kinase inhibitors (TKIs) shows good therapeutical effect in CML patients, but mutations in CML patients genotypes are now the new challenge to TKIs therapy and in the CML clinic, once approximately 20–30% of patients do not respond to TKI from first-generation
[58][60][61].