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KRAS-driven non-small cell lung cancer has been a historically difficult subtype to treat, despite being one of the most common oncogene-driven mutations in lung cancer. Prognosis for KRAS-driven lung cancers has been poor in comparison to those driven by other oncogenes, such as EGFR or ALK, particularly due to the lack of small molecule inhibitors developed to target mutant KRAS.

One of the main challenges in targeting KRAS is the specificity for the drug to target mutant KRAS and spare wild-type, preventing toxicities. Additionally, the RAS proteins often do not have suitable binding sites to which small molecule inhibitors can attach.

Blockade of downstream pathways has also been difficult and clinically ineffective. In lung cancer, driver mutations of KRAS most commonly occur on codon 12 and are predominantly G12C mutations. Direct inhibitors of mutant KRAS^G12C bind to a specific allosteric pocket in the enzyme and turn it in the off state.

Recently the FDA approved sotorasib for KRAS^G12C-mutated lung cancer. It had a 36% response rate, which is more than double the typical response rates expected with cytotoxic chemotherapy in this subtype.

The recent publication by Dr. Jia Luo et al. in the highlights the challenges in targeting KRAS mutations in lung cancer. The article describes the discovery of direct KRAS inhibitors as a breakthrough in precision oncology. Direct inhibitors such as sotorasib are irreversible allosteric inhibitors of KRAS, thus locking the enzyme in the inactive state.

Several similar compounds are now in development, and this publication highlights several successes as well as challenges in drug development against KRAS. Initiation of a KRAS inhibitor should be a priority in treating patients with advanced lung cancer with the appropriate mutations.

Future studies should raise the question of whether combination therapy with small molecule inhibitors and immune checkpoint inhibitors (such as in renal cell carcinoma) is a viable treatment option for KRAS-mutant lung cancers, since histologically KRAS mutations often confer a higher inflammatory state and tumor mutational burden.

Rajasree Pia Chowdry, MD, is assistant professor of clinical medicine in the Section of Hematology/Oncology at LSU Health Sciences Center, Louisiana Cancer Research Center, in New Orleans.

Read the review here and an interview about it here.