Abstract

DECIPHERING THE MCL-1 GENE: MOLECULAR PATHWAYS AND THERAPEUTIC IMPLICATIONS IN NSCLC

Mohammed Mubashir*, Vivek D., Shahin Muhammed T. K. and Mubeena Thousiya A. P.

Abstract

In the quest to elucidate the intricacies of non-small cell lung cancer (NSCLC), the MCL-1 gene emerges as a critical regulator of cellular fate, influencing apoptotic pathways and offering a promising target for therapeutic intervention. We begin with an introduction to the historical isolation and functional insights of the MCL-1 gene, establishing its significance as a cornerstone in apoptotic regulation. The classification of BCL-2 family proteins sets the stage for understanding MCL-1 variants and their distinct roles in cellular survival and oncogenesis. The review explores the structural dynamics of MCL-1 and its impact on apoptotic signalling, highlighting the potential of modulating MCL-1 splicing as a therapeutic strategy. We examined the PI3K/AKT/mTOR and EGFR pathways as conduits for MCL-1-mediated survival in NSCLC, and the targeting of MCL-1 in KRAS-mutant lung adenocarcinoma as a therapeutic opportunity. The circACC1/miR-29c-3p/MCL-1 axis is presented as a novel target for controlling NSCLC proliferation, while the compensatory role of MCL-1 in TP53-deficient lung cancer is discussed. The complex interplay of LUCAT1, SRSF1, and MCL-1 in NSCLC pathophysiology and strategies to overcome MCL-1 mediated resistance, such as targeting the mTORC1/eIF4E pathway. MCL-1’s involvement in HR DNA repair and replication stress sensitization is analysed, along with the integration of survival and apoptotic signalling pathways by MCL-1 in NSCLC. Finally, we consider the influence of MCL-1 on the transcriptional regulation of tumour suppressor p73, the interplay of PTEN and MCL-1 in EGFR-mutated NSCLC, the role of ER stress-induced MCL-1 in NSCLC pathogenesis, and the HIF pathway’s role in MCL-1 upregulation.

Keywords: Non-small cell lung cancer, Myeloid cell leukaemia-1, B-cell lymphoma 2.