Translational relevance of SOS1 targeting for KRAS‐mutant colorectal cancer

Abstract

It has been challenging to target mutant KRAS (mKRAS) in colorectal cancer (CRC) and other malignancies. Recent efforts have focused on developing inhibitors blocking molecules essential for KRAS activity. In this regard, SOS1 inhibition has arisen as an attractive approach for mKRAS CRC given its essential role as a guanine nucleotide exchange factor for this GTPase. Here, we demonstrated the translational value of SOS1 blockade in mKRAS CRC. We used CRC patient‐derived organoids (PDOs) as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406. A combination of in silico analyses and wet lab techniques was utilized to define potential predictive markers for SOS1 sensitivity and potential mechanisms of resistance in CRC. RNA‐seq analysis of CRC PDOs revealed two groups of CRC PDOs with differential sensitivities to SOS1 inhibitor BI3406. The resistant group was enriched in gene sets involving cholesterol homeostasis, epithelial−mesenchymal transition, and TNF‐α/NFκB signaling. Expression analysis identified a significant correlation between SOS1 and SOS2 mRNA levels (Spearman's ρ 0.56, p < 0.001). SOS1/2 protein expression was universally present with heterogeneous patterns in CRC cells but only minimal to none in surrounding nonmalignant cells. Only SOS1 protein expression was associated with worse survival in patients with RAS/RAF mutant CRC (p = 0.04). We also found that SOS1/SOS2 protein expression ratio >1 by immunohistochemistry (p = 0.03) instead of KRAS mutation (p = 1) was a better predictive marker to BI3406 sensitivity of CRC PDOs, concordant with the significant positive correlation between SOS1/SOS2 protein expression ratio and SOS1 dependency. Finally, we showed that GTP‐bound RAS level underwent rebound even in BI3406‐sensitive PDOs with no change of KRAS downstream effector genes, thus suggesting upregulation of guanine nucleotide exchange factor as potential cellular adaptation mechanisms to SOS1 inhibition. Taken together, our results show that high SOS1/SOS2 protein expression ratio predicts sensitivity to SOS1 inhibition and support further clinical development of SOS1‐targeting agents in CRC.

From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies

“…In both cases, numerous other genetic and epigenetic molecular partners can modify the activity of c-kit and KRAS, thereby influencing the initial response or the development of secondary resistance. Some of these partners for c-kit include Grb2, Grb7, Grb10, Shc, Gab2, Src, and for KRAS, Grb2, RASGEF, and SOS1 [ 99 , 100 , 101 ]. The “lateral” heterogeneity of these factors can certainly influence and condition different responses both within the same tumor and, even more so, across different tumors.…”

Development of PROTACS degrading KRAS and SOS1

“…The CRBN is an E3 ligase regarded to provide better oral availability in contrast to the VHL ligase. Furthermore, the short linker offers a rigid PROTAC structure that efficiently targets mutant KRAS in CRC [ 39 ].…”