Biology subjects

Daley, B. R.

Publications and source records attributed to Daley, B. R..

3 recordsLinked to original sources

bioRxiv2023

SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma

Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limits the clinical effectiveness of G12Cis, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci in situ. SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations. SignificanceThe SOS1 inhibitor BI-3406 both inhibits intrinsic/adaptive resistance and targets drug tolerant persister cells to limit the development of acquired resistance to clinical KRASG12C inhibitors in lung adenocarcinoma cells.

cancer biology↗

bioRxiv2023

In situ modeling of acquired resistance to RTK/RAS pathway targeted therapies

Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Preclinical studies that identify synergistic combinations enhance therapeutic efficacy to target intrinsic resistance, however, methods to study acquired resistance in cell culture are lacking. Here, we describe an in situ resistance assay (ISRA), performed in a 96-well culture format, that models acquired resistance to RTK/RAS pathway targeted therapies. Using osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show acquired resistance can be reliably modeled across cell lines with objectively defined osimertinib doses. We further show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using two distinct SHP2 inhibitors. Similar to patient populations, isolated osimertinib-resistant populations showed resistance via enhanced activation of multiple parallel RTKs so that individual RTK inhibitors did not re-sensitize cells to osimertinib. In contrast, inhibition of proximal RTK signaling using the SHP2 inhibitor RMC-4550 both re-sensitized resistant populations to osimertinib. Similar, objectively defined drug doses were used to model resistance to additional RTK/RAS pathway targeted therapies including the KRASG12C inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance. HighlightsO_LIAcquired resistance to RTK/RAS pathway members can be modeled in situ C_LIO_LISHP2 inhibitors reduce the development of acquired osimertinib resistance C_LIO_LIIsolated osimertinib-resistant populations show hyperactivation of multiple RTKs C_LIO_LISHP2 inhibitors re-sensitize resistant populations to osimertinib treatment C_LI

cancer biology↗

bioRxiv2023

SOS2 regulates the threshold of mutant EGFR-dependent oncogenesis

Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance. One sentence summarySOS2 modulates the threshold of EGFR-PI3K signaling to regulate the efficacy of and resistance to osimertinib.

cancer biology↗