Available online 20 February 2024

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Historically, KRAS has been considered ‘undruggable’ inspite of being one of the most frequently altered oncogenic proteins in solid tumors, primarily due to the paucity of pharmacologically ‘druggable’ pockets within the mutant isoforms. However, pioneering developments in drug design capable of targeting the mutant KRAS isoforms especially KRASG12C-mutant cancers, have opened the doors for emergence of combination therapies comprising of a plethora of inhibitors targeting different signaling pathways. SHP2 signaling pathway, primarily known for activation of intracellular signaling pathways such as KRAS has come up as a potential target for such combination therapies as it emerged to be the signaling protein connecting KRAS and the immune signaling pathways and providing the link for understanding the overlapping regions of RAS/ERK/MAPK signaling cascade. Thus, SHP2 inhibitors having potent tumoricidal activity as well as role in immunomodulation have generated keen interest in researchers to explore its potential as combination therapy in KRAS mutant solid tumors. However, the excitement with these combination therapies need to overcome challenges thrown up by drug resistance and enhanced toxicity. In this review, we will discuss KRAS and SHP2 signaling pathways and their roles in immunomodulation and regulation of tumor microenvironment and also analyze the positive effects and drawbacks of the different combination therapies targeted at these signaling pathways along with their present and future potential to treat solid tumors.

Section snippetsRAS signaling pathway and its brief biological activity and importance in solid tumors

Ras is a small guanosine triphosphate (GTPase), ubiquitously expressed in all cells, and a member of the G protein (guanine nucleotide binding protein) family (Chen, Zhang, Qian, & Wang, 2021). GTPases are prime regulators that adds or removes a phosphate group to transmit signals within the cell by switching from an active (GTP) to inactive (GDP) state and vice versa (Chen et al., 2021). This activity of Ras is mainly regulated by three crucial factors: Guanosine nucleotide dissociation

KRAS structure and function

KRAS is the most frequently mutated Ras isoform in humans and is fatally associated with solid tumors such as nonsmall-cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) (Yang, Zhang, Huang, & Chu, 2023). KRAS homologue was first identified in human lung cancer cells and was located on the short arm of chromosome 12 (12p11.1–12p12.1) (McBride et al., 1983). The KRAS gene generates two similar protein isoforms, KRAS-4B and KRAS-4A, due to the splice

KRAS signaling in health and disease

KRAS protein with a molecular mass of 23.2 kDa, performs as the first trigger for the intracellular signaling pathways. In human cells, KRAS4B is profoundly expressed compared to KRAS4A, which has weaker expression (Jančík, Drábek, Radzioch, & Hajdúch, 2010). Protein tyrosine kinase receptors in healthy condition, triggers and activates the KRAS signaling pathways, by binding to the ligands and inducing oligomerization of the receptor (Lemmon & Schlessinger, 2010). PTPN11 encoding SHP2, is a

KRAS mutant solid tumors

Wild type KRAS is a tumor suppressor gene and is frequently found to mutated during tumor progression in many cancers (Jančík et al., 2010). KRAS mutations are predominantly found in NSCLC, CRC, PDAC, Low-Grade Serous Ovarian Carcinoma, and Endometrial Cancer (Indini et al., 2021).

KRAS inhibitors

The high incidence of occurrence and lack of drug binding pocket makes KRAS one of the most studied and challenging therapeutic targets. Typically, patients with KRAS-mutant solid tumors were treated with conventional chemotherapy, where median PFS of CRC patients was 11.6 months, and OS for NSCLC patients was approximately 2 years (Ceddia et al., 2022, Zocche et al., 2015).

Immunotherapy and targeted therapy are combinedly under research by scientists to effectively inhibit KRAS and its

KRAS targeted resistance

Acquired resistance can occur for reasons such as de novo mutations, enhanced autophagy, feedback mechanisms of associated effectors. There are two key mechanisms responsible for resistance against KRAS inhibitors: intrinsic resistance and acquired resistance.

KRAS and SHP2 pathways linked with immunomodulation and TME

The TME comprises of diverse range of cells- tumor cells, matrix-associated cells and immune cells. As our understanding of the TME continues to evolve, it becomes evident that comprehending the microenvironment extends beyond immune cells and tumor cells alone; it is crucial to also grasp their intercommunication. The intrinsic mechanisms of tumor cells can effectively orchestrate interactions between tumor cells and immune cells, thereby reshaping the tumor immune environment. This process

Structure and biological function of SHP2

Src homology phosphatase 2 (SHP2), a protein tyrosine phosphatase (PTP), is encoded by PTPN11 and plays a key role in the activation of intracellular signaling pathways such as KRAS pathway. SHP2 has two SH2 domains (N-SH2 and C-SH2), a protein-tyrosine phosphatase (PTP) domain, and a C-terminal domain with two tyrosine residues (Fedele et al., 2020). The tyrosine residues are the phosphorylation site, such as tyrosine 542 and 580, and acts as a binding site GRB2-SOS1 complex and recruits it to

Combination of SHP2 inhibitors with other drugs in modulating KRAS driven solid tumours

SHP2i are also being tested with various combinations of drugs and inhibitors are being tested in several tumors which show hyperactivity of the RAS/ERK pathway. The immune-modulatory effects of SHP2is can be characterized systematically in genetically defined, immune- competent indigenous or orthotopic tumor models that resemble closely to human cancers might provide important insights into judicious combination of these agents. Many such combination therapies under clinical trials and active

Future directions

Safety and efficacy pose the biggest challenge in the use of SHP2i as a monotherapy or as part of a combination regimen more so because SHP2is are not well tolerated on their own. As such, evaluation of SHP2is have been done in a number of schedules to improve its tolerability such as: one big dose once per week; two days on followed by several days off;or three days on, 4 days off; or even two weeks on, one week off.” The current scenario still depicts that the combination strategy results in

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