Response and Resistance to RAS Inhibition in Cancer

Abstract

RAS inhibition has the potential to transform cancer treatment for many patients. The landscape of RAS inhibitor therapies is rapidly evolving, with two mutant-selective KRAS inhibitors now approved and multiple other mutant-selective, pan-KRAS, and pan-RAS inhibitors in development. However, monotherapy efficacy has been limited by primary and acquired resistance. In this article, we review preclinical and clinical data on RAS inhibition in cancer and describe multiple genetic and nongenetic mechanisms of resistance. Moreover, we highlight future opportunities for the design of rational combination therapy strategies, which will ultimately be needed to overcome resistance and enhance the efficacy of these promising treatments.

Significance: RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance. Development of best-in-class inhibitors, with optimal potency, selectivity, and pharmacokinetic properties, as well as effective and tolerable combination therapies will be needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy.

Figure 1. RAS signaling pathway.

A) Overview of the core RAS signaling pathway, demonstrating activation of both MAPK and PI3K signaling upon RAS activation. B) Overview of putative resistance mechanisms to KRAS inhibitors. Genes and transcriptional programs with alterations associated with resistance are highlighted. See Supplemental Table 1 for specific mutations associated with acquired resistance in patients.

Figure 2. Landscape of resistance mechanisms identified in patient samples.

Patient data collated from 10 publications (–16,32,81,102). See Supplemental Table 1 for per-patient breakdown of data. A) Breakdown of the number of alterations observed in patients with acquired resistance. B) Frequency that a gene/pathway is found newly mutated in patients with acquired resistance (graph contains all patients shown in Figure 2A; n=209). C) Breakdown of alterations observed in patients with acquired resistance and only one new mutation observed at time of resistance (graph contains only patients shown in green in Figure 2A; n=51). D) Number of genetic mutations identified by tumor type.

Figure 3. Therapeutic approach targeting cancer cell states.

A) Cells may occupy a spectrum of states with differing sensitivity or resistance to KRAS inhibition. Boxes highlight features of states identified from preclinical and clinical studies. B) Heterogeneous tumors may develop transcriptomic states resistant to KRAS inhibitors through multiple mechanisms, including selection for drug-resistant states by KRAS inhibitors and acquisition of transcriptional and/or genetic alterations driving cell state transitions to resistant states. C) KRAS inhibitors may be combined with cell state-targeting therapies with multiple potential MOAs, including therapies that promote KRAS inhibitor-sensitive states by inducing cells into sensitive states or preventing transition to KRAS inhibitor-resistant states, or therapies that directly kill KRAS inhibitor-resistant states.

Figure 4. KRAS inhibitor combination partners.

Potential approaches to combinatorial treatment with KRAS inhibitors representing a wide variety of therapeutic opportunities to maximize depth and duration of response and to overcome resistance.

Figure 5. Novel target identification.

Successful discovery of new therapeutic targets and development of novel KRAS inhibitor combination therapy approaches will require a systematic approach starting with the patient. The collection of tumor biopsies, ideally longitudinally over the course of treatment and progression, will yield clinically relevant data and models, which can be interrogated with cutting edge tools for biological investigation. Ultimately, the identification of tumor intrinsic vulnerabilities, cell surface targets, and neoantigens will yield novel therapeutic opportunities.