THZ1: Towards KRAS mutation-based precision medicine against pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable global challenge, with a grim prognosis and limited treatment options.¹ Prior to the advent of molecular targeted therapies, patients with PDAC typically received chemotherapy and surgical resection, with limited efficacies.² Genetic analyses have revealed that KRAS mutation importantly drives the pathogenesis of PDAC, prompting an increasing number of investigations into the potential of targeted therapies addressing this genetic alteration.^{3, 4} Recent advances in molecular targeted therapies, in particular Cyclin Dependent Kinase inhibitors, have shown promise in preclinical studies.^{5, 6}

The recent study by Huang et al.⁷ presented a compelling application for the targeted agent THZ1, a small-molecule covalent CDK7/12/13 inhibitor, and provided intriguing insights into its efficacy. THZ1 demonstrated differential inhibitory effects based on specific KRAS mutant subtypes and showed selective efficacy against PDAC harbouring the KRAS-G12V mutation compared to cancer with the KRAS-G12D mutation.

Huang et al.’s study⁷ employed a combination of in vitro and in vivo models to demonstrate that THZ1 was more effective in inhibiting KRAS-G12V PDAC. The importance of the PI3K/AKT/mTOR signalling pathway in KRAS mutation-driven pancreatic cancer has been previously highlighted.⁸ A previous study⁹ showed that in Ewing sarcoma, THZ1 reduced the phosphorylation of RNA polymerase II (RNAPOLII) by inhibiting CDK7 activity, which attenuated transcriptional activity, and that THZ1 inhibited the PI3K/AKT/mTOR signalling pathway by affecting the binding of H3K27ac to PIK3CA, which encodes the catalytic subunit of PI3K.

The present study⁷ further explored how THZ1 differentially inhibited PDAC cells by affecting this pathway: THZ1 inhibited KRAS-G12V PDAC cells through the inhibition of RNAPOLII phosphorylation, PIK3CA activity, and AKT and mTOR phosphorylation, with enhanced PTEN expression, thus weakening the proliferation of cancer cells. This specificity represents a significant advance, as it paves the way for personalized management of PDAC.

The study⁷ discovered that the discrepancies in the sensitivity of different PDAC subtypes to THZ1 were related to the differential effects of THZ1 on the activity of super-enhancers (SEs). THZ1 significantly inhibited the activity of SEs marked by H3K27ac, which bound to PIK3CA, in PDAC cells with the KRAS-G12V mutation, whereas it had a minor effect on SEs in cells with the KRAS-G12D mutation.

Huang et al.’s study⁷ is of particular interest, given the critical role of KRAS mutations in the pathogenesis of PDAC. The differential responses of cancers harbouring the KRAS-G12V and KRAS-G12D mutations to THZ1 highlight the importance of molecular profiling in guiding therapeutic decisions. Concurrently, this study⁷ mechanistically elucidated the selective effects of THZ1 on RNAPOLII phosphorylation and SE activity, thereby paving the way for a deeper comprehension of its precise therapeutic potential.

The implications of Huang et al.’s findings⁷ for clinical practice are profound. They suggest that genetic profiling, particularly the identification of specific KRAS mutation subtypes, should be an integral part of the diagnostic and therapeutic decision-making processes in PDAC. By aligning the genetic profile with specific molecular inhibitors, clinicians can tailor treatments for individual patients, potentially enhancing therapeutic efficacy while minimizing toxicity. This approach not only streamlines clinical interventions but also underscores the shift towards personalized oncology for PDAC.

Notably, the scope of this study⁷ was limited to specific KRAS mutations and further studies are needed to explore the efficacies of THZ1 in PDACs with a wider range of genetic alterations. Inactivating mutations in genes including CDKN2A/p16, TP53 and SMAD4¹⁰ also synergize with KRAS mutations, which subsequently leads to aggressive PDAC growth. Future studies should expand the effects of THZ1 on other mutations and explore its potential in combination therapies. It is also critical to investigate the long-term safety and efficacy of THZ1 and its impact on patient quality of life. The development of liquid biopsy biomarkers that predict response to THZ1 with high specificity is necessary for pancreatic cancer,³ which can help with the development of personalized therapeutic regimens. The understanding of the mechanism of action of THZ1 should also be further enhanced through molecular-level experiments, to identify the key genes and proteins that are altered following THZ1 treatment.

The field of precision oncology in PDAC is currently experiencing a transformative phase. The grim prognosis historically linked with this cancer is being challenged by groundbreaking genetic insights. Huang et al.’s study⁷ highlights the promise of treatment strategies that are tailored to the genetic profile of individual cancers. As more intricate details of PDAC's genetics are uncovered, the roles of molecular diagnostics and therapeutics become increasingly significant. The identification of specific genetic aberrations is pivotal in facilitating the discovery of bespoke targeted therapeutic regimens. This integration of precise diagnostic tools with targeted therapies is poised to markedly improve clinical outcomes, offering new hope to PDAC patients who have long faced limited treatment options.

Together, the research presented by Huang et al.⁷ is a landmark in the ongoing endeavour to tailor cancer therapy to the genetic underpinnings of each patient's cancer and marks a significant step towards precision medicine in PDAC. The selective efficacy of THZ1 against KRAS-G12V PDAC provides a blueprint for future research and clinical trials. The future of PDAC treatment lies in the ability to precisely address molecular aberrations, a goal that is now closer to realization thanks to this significant research.⁷ As the field of precision oncology continues to evolve, targeted therapies like THZ1 hold the promise of transforming PDAC care.

Conception and design: Mancang Gu, Yan Shi and Lei Huang. Writing, review, and/or revision of the manuscript: Yansong Qin, Mancang Gu, Yan Shi and Lei Huang. Administrative, technical, or material support (i.e. reporting or organizing data and constructing databases): Mancang Gu, Yan Shi and Lei Huang. Study supervision: Mancang Gu, Yan Shi and Lei Huang. All authors approved the manuscript for submission and publication.

The authors declare no conflict of interest.

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