bims-pimaco 2023-11-19 papers

Cell Chem Biol. 2023 Nov 16. pii: S2451-9456(23)00368-9. [Epub ahead of print]30(11): 1334-1336

Addicted to proteostasis: How KRAS-driven cancers acquire resistance to clinical KRAS inhibitors.

The development of KRAS inhibitors was a remarkable feat, yet their efficacy is limited by inevitable resistance. In the September issue of Science, Lv et al.1 demonstrate how KRAS-driven cancers rewire signaling to restore protein homeostasis and acquire resistance to KRAS inhibitors with implications for novel combination therapeutic strategies.

DOI: https://doi.org/10.1016/j.chembiol.2023.10.007

Proc Natl Acad Sci U S A. 2023 Nov 21. 120(47): e2313137120

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.

Brianna R Daley, Heidi M Vieira, Chaitra Rao, Jacob M Hughes, Zaria M Beckley, Dianna H Huisman, Deepan Chatterjee, Nancy E Sealover, Katherine Cox, James W Askew, Robert A Svoboda, Kurt W Fisher, Robert E Lewis, Robert L Kortum.

KRAS is the most commonly mutated oncogene. Targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance. Survival of drug-tolerant persister cells within the heterogeneous tumor population and/or acquired mutations that reactivate receptor tyrosine kinase (RTK)/RAS signaling can lead to outgrowth of tumor-initiating cells (TICs) and drive therapeutic resistance. Here, we show that targeting the key RTK/RAS pathway signaling intermediates SOS1 (Son of Sevenless 1) or KSR1 (Kinase Suppressor of RAS 1) both enhances the efficacy of, and prevents resistance to, the MEK inhibitor trametinib in KRAS-mutated lung (LUAD) and colorectal (COAD) adenocarcinoma cell lines depending on the specific mutational landscape. The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting spheroid-initiating cells in KRASG12/G13-mutated LUAD and COAD cell lines that lacked PIK3CA comutations. Cell lines with KRASQ61 and/or PIK3CA mutations were insensitive to trametinib and BI-3406 combination therapy. In contrast, deletion of the RAF/MEK/ERK scaffold protein KSR1 prevented drug-induced SIC upregulation and restored trametinib sensitivity across all tested KRAS mutant cell lines in both PIK3CA-mutated and PIK3CA wild-type cancers. Our findings demonstrate that vertical inhibition of RTK/RAS signaling is an effective strategy to prevent therapeutic resistance in KRAS-mutated cancers, but therapeutic efficacy is dependent on both the specific KRAS mutant and underlying comutations. Thus, selection of optimal therapeutic combinations in KRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations.

Keywords: KSR1; RAS; SOS1; resistance; trametinib

DOI: https://doi.org/10.1073/pnas.2313137120

ACS Med Chem Lett. 2023 Nov 09. 14(11): 1493-1495

KRAS-Degrading Compounds: A Novel Approach to Treat Cancer by Targeting Both Wild-Type and Mutated KRAS Forms.

Robert B Kargbo.

KRAS, a critical gene involved in cellular processes, can initiate tumor formation when mutated. These mutations occur in about 20-30% of all human cancers, linking KRAS particularly to lung, colorectal, and pancreatic cancers. Its "undruggable" reputation, owing to the difficulty in inhibiting its activity, is being challenged by promising developments. Notably, covalent inhibitors such as sotorasib show success in binding to specific KRAS mutations. Also, PROTACs, an emerging technology, effectively reduce protein levels in the cell, inspiring similar strategies using KRAS-degrading compounds. Novel combination therapies have demonstrated improved anti-tumor effects. This Patent Highlight reveals exemplary KRAS-degrading compounds with anti-tumor activity, effective against both wild-type and mutated KRAS. They present desirable pharmacological properties, promising a revolution in cancer treatment upon further clinical investigation.

DOI: https://doi.org/10.1021/acsmedchemlett.3c00442

Br J Cancer. 2023 Nov 15.

APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.

BACKGROUND: Aberrant WNT/β-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, β-catenin repressors. Tankyrase inhibitors block WNT/β-catenin signaling and colorectal cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor-resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity.
METHODS: Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582.
RESULTS: Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active β-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor-resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a β-catenin-independent manner.
CONCLUSIONS: APC/PIK3CA mutations and β-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

DOI: https://doi.org/10.1038/s41416-023-02484-8