Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance

Abstract

Background Acute myeloid leukemia (AML) remains a devastating disease with a 5-year survival rate of less than 30%. AML treatment has undergone significant changes in recent years, incorporating novel targeted therapies along with improvements in allogeneic bone marrow transplantation techniques. However, the standard of care remains cytarabine and anthracyclines, and the primary hindrance towards curative treatment is the frequent emergence of intrinsic and acquired anticancer drug resistance. In this respect, patients presenting with chemoresistant AML face dismal prognosis even with most advanced therapies. Herein, we aimed to explore the potential implementation of the characterization of chemoresistance mechanisms in individual AML patients towards efficacious personalized medicine. Methods Towards the identification of tailored treatments for individual patients, we herein present the cases of relapsed AML patients, and compare them to patients displaying durable remissions following the same chemotherapeutic induction treatment. We quantified the expression levels of specific genes mediating drug transport and metabolism, nucleotide biosynthesis, and apoptosis, in order to decipher the molecular mechanisms underlying intrinsic and/or acquired chemoresistance modalities in relapsed patients. This was achieved by real-time PCR using patient cDNA, and could be readily implemented in the clinical setting. Results This analysis revealed pre-existing differences in gene expression levels between the relapsed patients and patients with lasting remissions, as well as drug-induced alterations at different relapse stages compared to diagnosis. Each of the relapsed patients displayed unique chemoresistance mechanisms following similar treatment protocols, which could have been missed in a large study aimed at identifying common drug resistance determinants. Conclusions Our findings emphasize the need for standardized evaluation of key drug transport and metabolism genes as an integral component of routine AML management, thereby allowing for the selection of treatments of choice for individual patients. This approach could facilitate the design of efficacious personalized treatment regimens, thereby reducing relapse rates of therapy refractory disease.

Lin28A/CENPE Promoting the Proliferation and Chemoresistance of Acute Myeloid Leukemia

“…The prognosis for AML patients remains poor, with a 5-year survival rate of <30%, even with novel therapeutic agents ( 8 ). AML is partially triggered by dysregulated cell proliferation, which involves cell cycle modulation and DNA reparation.…”

“…The dysregulated cell cycle could induce raised proliferation, which predisposes leukemic cells to gain mutations and may privilege chemoresistant leukemic transformation (4)(5)(6). Cell cycle-specific agent cytarabine (Ara-C) and cell cycle-nonspecific agents anthracycline chemotherapeutics are the standard treatment of AML in both induction and consolidation therapies, but still a proportion of patients present intrinsic or acquired chemotherapy resistance (7,8). Thus, there is an urgent need for new targets and therapeutic approaches to treat chemoresistant AML.…”

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

“…Since 1970, the standard of care for AML patients has been based on chemotherapeutic treatment (the '3 + 7' regimen, combining daunorubicin and cytarabine), resulting in 5-year survival rates of 40-45% for patients up to 55 years, that decrease to 30-35% for patients up to 60 and may become as low as 10-15% in older patients [7,8]. Moreover, the relapsed disease after complete remission still represents the most common cause of death among AML patients, and it is associated with increased molecular complexity that often contributes to treatment failure [9,10]. Therefore, unraveling the cytogenetic and molecular profile of AML has improved the therapeutic opportunities leading to the development of new targeted therapies.…”

Modulating undruggable targets to overcome cancer therapy resistance

“…But even when the drug reaches its cellular target at a sufficient concentration, the cancer cell might still escape the therapeutic effects reactivating the same signalling pathway further downstream or activating alternative signal cascades (Paraiso et al, 2011). In addition, enhanced DNA damage repair (Lord and Ashworth, 2012) and dysfunctional apoptosis signalling (Mohammad et al, 2015) (Shahar and Larisch, 2020;Levin, et al, 2021;Gao, et al, 2021) can limit the efficacy of anti-cancer drugs. Several of these resistance mechanisms might co-exist in different cells that comprise a tumor.…”