Overcoming Therapeutic Resistance by Targeting Oncogene-Driven and Targeted-Therapy Induced Cancer Dependencies

Wood, Kris

Ali, Moiez

2021-05-19T18:07:30Z

2022-05-17T08:17:19Z

2020

Molecular Cancer Biology

Targeted therapies rarely yield complete tumor responses, and the residual cancer cells that survive upfront treatment act as a reservoir from which eventual resistant disease emerges. Here, we explore several clinically relevant models of disease resistance, with special attention placed on KRAS-driven colorectal cancer (CRC) and EGFR-driven non-small-cell lung cancer (NSCLC).

First, we note that KRAS mutations drive resistance to diverse targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRASQ61mutations that function even when protein expression is low. Finally, we show that cancer cells upregulate translation to facilitate KRASG12-driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.

Next, we demonstrate that targeted therapies induce DNA double strand breaks and consequent, ATM-dependent DNA repair in tumor cells that survive upfront treatment. This DNA damage response, observed in both laboratory models and human patients, is driven by a pathway involving the sub-lethal activation of executioner caspases 3 and 7 and the downstream caspase-activated DNase (CAD). As a consequence, tumor cells that survive upfront treatment harbor a synthetic dependence on ATM, and combined treatment with targeted therapies and a selective ATM kinase inhibitor eradicates these cells, leading to more penetrant and durable responses in in vitro and in vivo models of EGFR-mutant NSCLC. Finally, rare patients with EGFR-mutant NSCLC harboring co-occurring, loss-of-function mutations in ATM show evidence of extended progression-free survival relative to patients lacking deleterious ATM mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapy paradigms.

Combined, these studies provide mechanistic-based rationale for pharmacological targeting of tumor-specific processes that may overcome intrinsic and/or acquired resistance states, serving as potential novel therapeutic options for genetically defined subsets of cancer patients.

https://hdl.handle.net/10161/22949

Molecular biology

Pharmacology

Cancer

DNA damage response

Protein translation

Targeted therapy

Therapeutic resistance

Overcoming Therapeutic Resistance by Targeting Oncogene-Driven and Targeted-Therapy Induced Cancer Dependencies

Dissertation

11.901369863013699