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Unveiling the role of KRAS in tumor immune microenvironment

Miao Xu¹, Xing Zhao², Ti Wen¹

¹Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie

|January 3, 2024

Abstract:

Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a "hot" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a "colder" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.

Insights

Kirsten rat sarcoma viral oncogene (KRAS) mutations drive cancer and influence the tumor immune microenvironment. KRAS inhibitors show promise, especially when combined with immune checkpoint inhibitors, to overcome resistance.

Area of Science:

Oncology
Cancer Immunology
Molecular Biology

Background:

Kirsten rat sarcoma viral oncogene (KRAS) is a frequently mutated oncogene in cancers like NSCLC, CRC, and PDAC.
KRAS mutations promote tumor growth and create an immunosuppressive tumor microenvironment (TME) by increasing PD-L1 and TMB, and recruiting suppressive immune cells.
Despite KRAS's
undruggable
status, KRAS-mutated NSCLC patients show better responses to immune checkpoint inhibitors (ICIs).

Purpose of the Study:

To explore the intricate relationship between KRAS mutations, the tumor microenvironment, and responses to cancer therapies.
To investigate the impact of KRAS co-mutations on TME characteristics and immunotherapy outcomes.
To evaluate the potential of KRAS inhibitors, particularly KRAS G12C inhibitors, and combination strategies for cancer treatment.

Main Methods:

Review and analysis of existing literature on KRAS mutations, TME, and treatment responses.
Examination of immune signatures associated with different KRAS alterations and co-mutations.
Evaluation of the efficacy and resistance mechanisms of KRAS inhibitors and combination therapies, including with ICIs and SHP2 inhibitors.

Main Results:

KRAS mutations create a suppressive TME but can enhance ICI response in NSCLC.
Co-mutations with KRAS, such as TP53, significantly influence TME profiles and immunotherapy outcomes.
KRAS G12C inhibitors improve outcomes in NSCLC and can restore the TME, suggesting combination potential with ICIs.
Drug resistance remains a challenge for KRAS inhibitors, highlighting the need for novel combination strategies.

Conclusions:

KRAS mutations are critical drivers of oncogenesis and immune evasion, presenting unique therapeutic opportunities.
Understanding KRAS co-mutation status is essential for predicting immunotherapy response.
Combination therapies, including KRAS inhibitors with ICIs or SHP2 inhibitors, hold significant promise for overcoming resistance and improving patient outcomes.

Read full analysis

Keywords:

Co-mutation Immunotherapy KRAS KRAS inhibitor Resistance

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