IA03 Therapeutic Approaches in KRAS-Driven Non-Small Cell Lung Cancer

Abstract

RAS mutations (KRAS, HRAS, and NRAS) are the most common oncogenic drivers in non-small cell lung cancer (NSCLC). In metastatic NSCLC, KRAS mutations are associated with worse overall survival compared with KRAS wild-type tumors. They are also unique among the targetable alterations in NSCLC in that they are often associated with a patient smoking history. Though targeted therapies have led to significant improvements in survival of NSCLC patients with activating alterations in EGFR, ALK, ROS1, and BRAF, effective therapies targeting the RAS pathway have been elusive. The challenge in targeting KRAS reflects the complex biology of the RAS signaling pathway. KRAS proteins are membrane-bound effector proteins that link cell surface receptors to downstream growth and proliferation pathways. KRAS proteins are cytosolic protein that are linked to the cell membrane. They cycle between an inactive GDP-bound form and an active GTP-bound form with high affinity. Cycling between active and inactive states is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). When constitutively active, such as in KRAS mutated NSCLC, overlapping downstream growth and proliferation pathways such as PI3K/AKT, RAF/MEK/ERK, and RALGOS/RAL/RLBP1 become activated. Part of the challenge in blocking the oncogenic signaling pathways that originate from KRAS mutations is the crosstalk and redundancy within the pathway. Additionally, the comutational landscape of KRAS mutated NSCLC impacts responses to treatment and can have independent oncogenic activity, further adding to the challenge of blocking oncogenic signaling. Numerous therapeutic tactics have attempted to target this signaling pathway; however, until recently there has been limited success. Therapeutic approaches for KRAS-positive tumors include 1) targeting of the membrane attachment of the KRAS protein, 2) direct targeting of KRAS and its coactivation partners, 3) targeting of downstream and parallel growth and activation pathways, 4) targeting of synthetic lethal interactions, and 5) utilization of immunotherapy. Within and between each of these categories there are also combination therapies being developed. Despite the inherent complexity in developing treatments for KRAS mutated NSCLC, there are now multiple promising strategies in development that may change the treatment landscape of this disease. In this session, we will explore the background and current landscape of the therapeutic approaches for KRAS mutated NSCLC.