Evolving Molecular Drug Targets in Pancreatic Cancer: An Updated Review.

Pancreatic Cancer (PC) remains one of the most aggressive and lethal malignancies with an extremely low survival rate. Existing conventional therapies such as surgery, chemotherapy, radiotherapy, and immunotherapy have demonstrated limited effectiveness in significantly improving overall survival outcomes, largely due to the unique and hostile Tumour Microenvironment (TME) of PC. The TME is characterised by a desmoplastic stroma, an immunosuppressive, hypovascular, and hypoxic microenvironment, which collectively contribute to therapeutic failure. These features not only limit effective drug delivery but also promote tumour progression and treatment resistance. In recent years, the emergence of molecular targeted therapies has enabled the targeting of aberrantly activated kinases or other highly expressed targets in PC, such as KRAS, CDKN2A, TP53, SMAD4, epigenetic regulators, and signalling pathways. However, the clinical efficacy of many targeted agents remains limited, highlighting the complexity of tumour heterogeneity and adaptive resistance mechanisms. These limitations underscore the need to develop more effective therapeutic strategies for PC. Advances in precision oncology, immunotherapy, and patient derived models offer promising opportunities to improve the understanding of tumour biology, elucidate mechanisms underlying therapeutic response and resistance, and identify novel treatment strategies tailored to individual patients. Herein, this review aims to provide an updated overview of the current state of molecular therapies and the underlying molecular mechanisms and oncogenic pathways that contribute to PC initiation, development, progression and metastasis.