KRAS Inhibitors– yes but what next? Direct targeting of KRAS– vaccines, adoptive T cell therapy and beyond

Misako Nagasaka,Bindu Potugari,Alexis Nguyen,Ammar Sukari,Asfar S Azmi,Sai-Hong Ignatius Ou

doi:10.1016/j.ctrv.2021.102309

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.

Highlights

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a protooncogene of the RAS-mitogen-activated protein kinase (MAPK) pathway
Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations [1]
Single agent ac tivity of adagrasib had an objective response of 22% (n = 10/45) while the combination therapy of adagrasib and cetuximab provided an objective response of 43% (n = 12/28) [30]. This has lead to a phase 3, open label randomized clinical trial KRSYTAL-10 which will compare the efficacy of MRTX849 in combination with cetuximab versus chemotherapy in the second line treatment in patient with colorectal cancer with KRASG12C mutation (NCT04793958)

Summary

Introduction

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a protooncogene of the RAS-MAPK pathway. There are other ongoing trials eval uating sotorasib as a monotherapy or in combination in KRAS G12C mutated lung cancer or other solid tumors (NCT04185883 [Codebreak 101]), NCT04667234 [expanded access], NCT04625647 [LUNGMAP], NCT04380753 [Codebreak 105 Chinese ethnic sensitivity study], NCT04185883).

Results

Conclusion