MECHANISMS OF RESISTANCE TO SMALL MOLECULE INHIBITORS

Abstract

The development of targeted small molecule inhibitors of key tumorigenic and survival mechanisms, especially those involved in the B-cell receptor (Bruton Tyrosine Kinase (BTK) and PI3-kinase (PI3K)) and apoptosis (BCL2) pathways, have transformed the treatment landscape for many indolent lymphoproliferative disorders. The relevant approved agents are: Ibrutinib, acalbrutinib and Zanubrutinib as covalent inhibitors, and Pirtobrutinib as a non-covalent inhibitor of BTK, Idelalisib as a PI3K inhibitor and Venetoclax as a BCL2 inhibitor. These agents have had the greatest impact in chronic lymphocytic leukemia (CLL) but also significant utility in mantle-cell lymphoma (MCL), Waldenström macroglobulinemia (WM) and marginal zone lymphoma (MZL). Focusing on CLL as the exemplar disease context, true primary resistance is uncommon and often reveals the presence of a transformed clone (Richter transformation). Emergence of secondary resistance increases with the duration of drug exposure and commonly involves the emergence and ultimate outgrowth of clones with acquired mutations in either the target gene (BTK or BCL2) or alternative activating or bypassing mutations or dysregulation in other pathway member genes which functionally mitigate the inhibitory action of the drug; examples are PLCɣ mutations downstream of BTK, or BCL-Xl or MCL1 as alternative anti-apoptotic molecules overcoming BCL2 inhibition. It is now recognised that there are often multiple sub-clones with a range of these acquired changes present simultaneously in varying proportions. These tumour restricted genomic mechanisms of resistance are often also accompanied by additional cell intrinsic metabolic and proliferation-related changes as well as micro-environmental adaptions assisting tumor cell survival. Another layer of complexity is being revealed with our increasing understanding that within the covalent BTK inhibitor drug class, the spectrum of acquired mutations differs between agents and there is variable cross-resistance of these mutations with the non-covalent inhibitor Pirtobrutinib that may influence treatment sequencing decisions. Although these pathway specific resistance mechanisms do not predict for intrinsic resistance to the other drug class (BTK vs. BCL2 inhibitors), early single-cell data suggest that “double class” resistant disease can involve both compound mutant clones (harboring both BTK and BCL2) mutations, or heterogeneous multi-clonal mechanisms. The mechanisms of acquired resistance to currently approved agents have significant implications both for clinical management and treatment sequencing decisions and the potential utility of novel agents targeting these same pathways (such as BTK-degraders BGB-16673 and NX-5984 and the BCL2 inhibitor sonrotoclax).

Keywords: chronic lymphocytic leukemia (CLL); indolent non-Hodgkin lymphoma

Potential sources of conflict of interest:

J. F. Seymour

Consultant or advisory role: Genor Bio, TG Therapeutics

Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Janssen, Roche

Other remuneration: Research Funding: AbbVie, BMS, Roche. Speaker's Bureau: AbbVie, AstraZeneca, BMS, Roche