bims-pimaco 2023-07-16 papers

Trends Pharmacol Sci. 2023 Jul 10. pii: S0165-6147(23)00129-3. [Epub ahead of print]

Isoform-selective targeting of PI3K: time to consider new opportunities?

Davide Cirillo, Marta Diceglie, Marc Nazaré.

Phosphoinositide-3-kinases (PI3Ks) are central to several cellular signaling pathways in human physiology and are potential pharmacological targets for many pathologies including cancer, thrombosis, and pulmonary diseases. Tremendous efforts to develop isoform-selective inhibitors have culminated in the approval of several drugs, validating PI3K as a tractable and therapeutically relevant target. Although successful therapeutic validation has focused on isoform-selective class I orthosteric inhibitors, recent clinical findings have indicated challenges regarding poor drug tolerance owing to sustained on-target inhibition. Hence, additional approaches are warranted to increase the clinical benefits of specific clinical treatment options, which may involve the employment of so far underexploited targeting modalities or the development of inhibitors for currently underexplored PI3K class II isoforms. We review recent key discoveries in the development of isoform-selective inhibitors, focusing particularly on PI3K class II isoforms, and highlight the emerging importance of developing a broader arsenal of pharmacological tools.

Keywords: PI3K; cancer; immunotherapy; isoform-selective inhibitors; thrombosis; toxicity

DOI: https://doi.org/10.1016/j.tips.2023.06.002

Oncologist. 2023 Jul 11. pii: oyad138. [Epub ahead of print]

Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review.

John H Strickler, Takayuki Yoshino, Kendall Stevinson, Christian Stefan Eichinger, Christina Giannopoulou, Marko Rehn, Dominik Paul Modest.

PURPOSE: A systematic literature review was conducted to estimate the global prevalence of Kirsten rat sarcoma virus gene (KRAS) mutations, with an emphasis on the clinically significant KRAS G12C mutation, and to estimate the prognostic significance of these mutations in patients with colorectal cancer (CRC).
DESIGN: Relevant English-language publications in the Embase, MEDLINE, and the Cochrane Library databases (from 2009 to 2021) and congress presentations (from 2016 to 2021) were reviewed. Eligible studies were those that reported the prevalence and clinical outcomes of the KRAS G12C mutation in patients with CRC.
RESULTS: A total of 137 studies (interventional [n = 8], post hoc analyses of randomized clinical trials [n = 6], observational [n = 122], and longitudinal [n =1]) were reviewed. Sixty-eight studies reported the prevalence of KRAS mutations (KRASm) in 42 810 patients with CRC. The median global prevalence of KRASm was 38% (range, 13.3%-58.9%) and that of the KRAS G12C mutation (KRAS G12C) 3.1% (range, 0.7%-14%). Available evidence suggests that KRASm are possibly more common in tumors that develop on the right side of the colon. Limited evidence suggests a lower objective response rate and inferior disease-free/relapse-free survival in patients with KRAS G12C compared with patients with KRASwt or other KRASm.
CONCLUSION: Our analysis reveals that KRAS G12C is prevalent in 3% of patients with CRC. Available evidence suggests a poor prognosis for patients with KRAS G12C. Right-sided tumors were more likely to harbor KRASm; however, their role in determining clinical outcomes needs to be investigated further.

Keywords: KRAS G12C; KRASm; colorectal cancer; global; prevalence; prognosis; systematic literature review

DOI: https://doi.org/10.1093/oncolo/oyad138

Trends Cancer. 2023 Jul 07. pii: S2405-8033(23)00110-3. [Epub ahead of print]

Beyond gene expression: how MYC relieves transcription stress.

Dimitrios Papadopoulos, Leonie Uhl, Stefanie Anh Ha, Martin Eilers.

MYC oncoproteins are key drivers of tumorigenesis. As transcription factors, MYC proteins regulate transcription by all three nuclear polymerases and gene expression. Accumulating evidence shows that MYC proteins are also crucial for enhancing the stress resilience of transcription. MYC proteins relieve torsional stress caused by active transcription, prevent collisions between the transcription and replication machineries, resolve R-loops, and repair DNA damage by participating in a range of protein complexes and forming multimeric structures at sites of genomic instability. We review the key complexes and multimerization properties of MYC proteins that allow them to mitigate transcription-associated DNA damage, and propose that the oncogenic functions of MYC extend beyond the modulation of gene expression.

Keywords: BRCA1; MYC; MYCN; PAF1 complex; RNA polymerase; double-strand break; topoisomerase; transcription replication conflict

DOI: https://doi.org/10.1016/j.trecan.2023.06.008