Drug resistance is reshaping lung cancer care—AACR 2026 may reveal what’s next
Industry Buzz
Heterogenous or compound mutations are various, including MET amplification, rare KRAS mutations, or transformations rarely. For ALK-mutated NSCLC patients, the most common tends to be G1202R mutation, for which the third-generation ALK inhibitor such as lorlatinib is preferred.
—Hina Khan, MD
Understanding how the tumor is changing in response to the therapy will determine the next steps in intervention... When additional mutations develop in the targets, if a countermeasure is not available for those mutations or lineage switching happens... chemotherapy is used as a fallback.
—Neil Bhowmick, PhD
Drug resistance remains a central challenge in non–small-cell lung cancer (NSCLC).
Data being presented at the AACR 2026 annual meeting highlight new mechanisms across targeted therapies and emerging strategies to address them.
Secondary mutations limit targeted therapy
Zongertinib is the only tyrosine kinase inhibitor (TKI) approved by the FDA for patients with HER2-mutant NSCLC. Targeted therapies are key in NSCLC management, but drug resistance is on the rise. Zongertinib, the only approved HER2 TKI, shows emerging resistance patterns.
New AACR data identify secondary HER2 mutations including S783C, C805S, and T862A. These mutations disrupt drug binding and limit efficacy, while retaining sensitivity to alternative HER2 inhibitors such as sevabertinib.[]
Neil Bhowmick, PhD, Professor of the Department of Medicine and Mark Goodson Chair in Oncology Research, puts this into context. “The mechanisms of resistance for the EGFR, ALK, HER2, KRAS are similar,” he says. “(1) The most common mechanism of resistance encountered is mutations in the respective target proteins themselves that make the antagonist ineffective; (2) bypass pathways including EGFR-activating mutations and MET amplification; (3) lineage/phenotypic changes in the tumor type, where the cancer may develop a mesenchymal phenotype or small cell lineage marker expression.”
He adds, “A common TKI used in the NSCLC population is EGFR inhibitors, as it accounts for about 15% of the US population, but can be as high as half of the East Asian population. The prevalence of the use of ALK and HER2 antagonists for the respective disease driver mutations is 5% to10% combined in NSCLC patients. Now, KRAS inhibitors are newer on the scene that address about 12% to-14% of the NSCLC population, although KRAS can be a driver of about a quarter of all NSCLC.”
ALK resistance extends beyond known pathways
ALK-rearranged disease continues to evolve under treatment pressure. A genome-wide CRISPR activation screen across more than 18,000 genes identified multiple resistance drivers, including EGFR, MET, FGFR1, and BCL2. These pathways promote survival through receptor tyrosine kinase signaling and anti-apoptotic mechanisms.[]
A separate CRISPR knockout study identified BMF loss as a key mechanism enabling survival of drug-tolerant persister cells. Low BMF expression correlated with poorer outcomes and reduced apoptosis under ALK inhibition.[]
Clinically, this aligns with what physicians are seeing. Hina Khan, MD, a board-certified hematologist-oncologist, added, “Heterogenous or compound mutations are various, including MET amplification, rare KRAS mutations, or transformations rarely. For ALK-mutated NSCLC patients, the most common tends to be G1202R mutation, for which the third-generation ALK inhibitor such as lorlatinib is preferred.”
KRAS G12C resistance follows evolutionary patterns
KRAS G12C–mutant tumors develop resistance through adaptive evolution. In vitro models exposed to sotorasib over multiple cycles developed robust resistance in most replicates. Resistant cells showed cross-resistance to EGFR and HER2 inhibitors, while gaining sensitivity to paclitaxel, indicating collateral vulnerabilities.[]
Gene expression analysis revealed activation of EMT, mTORC1, and inflammatory pathways, along with increasing heterogeneity over time.[]
Tumor ecology influences resistance behavior
Resistance is shaped by interactions between tumor cell populations. Resistant clones in KRAS models demonstrated increased baseline fitness and outcompeted sensitive cells even in the absence of drug. These ecological dynamics varied with drug dose, suggesting that dosing strategies may influence resistance trajectories.[]
Immune signaling contributes to TKI resistance
EGFR-mutant lung cancer shows resistance linked to immune signaling pathways. AACR data identify CHI3L1 as a regulator of PD-1 and PD-L1 expression through YAP and TAZ signaling. Dual targeting of CHI3L1 and immune checkpoints reduced resistance and immune tolerance in preclinical models.[]
Dr. Bhowmick discusses the importance of biomarker testing and repeated genomic profiling to address the issue of genomic resistance, saying, “Understanding how the tumor is changing in response to the therapy will determine the next steps in intervention….When additional mutations develop in the targets, if a countermeasure is not available for those particular mutations or lineage switching happens (determined often at the histologic level as opposed to genomic), sometimes chemotherapy is used as a fallback. In the case where drugs are available for the developing resistance (eg, EGFR or MET), those respective antagonists can be considered.”
Resistance can also be metabolic
Resistance is not limited to genetic changes. AACR data show intracellular cysteine accumulation directly inactivates covalent inhibitors through chemical sequestration. High SLC7A11 expression led to resistance to CDK7 inhibitors, while modulation of cysteine levels altered drug response.[]
In simple terms, drug efficacy depends on intracellular metabolic context, not only target engagement.
Combination therapies gain momentum
Single-agent strategies continue to fail in resistant disease. AACR findings support combination approaches. In MTAP-deleted tumors, the PRMT5 inhibitor AMG 193 showed variable activity across models, with both primary and acquired resistance observed. Combination with sotorasib restored sensitivity in KRAS G12C models resistant to monotherapy.[]
Antibody-drug conjugates (ADCs) are also evolving. Dual-payload ADCs targeting DNA damage response and cell cycle pathways demonstrated greater than three-fold improvements in efficacy compared to single payloads in resistant models.[]
Dr. Khan says she is optimistic, as the combination therapy approach “has already provided a good option in other mutation mechanisms. For example, using an EGFR bispecific antibody in a patient who progressed on an EGFR TKI is an effective treatment strategy.“
Dr. Bhowmick adds, “Combination therapies and ADCs clearly are making a case in addressing resistance or even limiting the development of certain resistance mechanisms."
However, he warns how toxicity is an important consideration for these therapies. “In the case of combination therapies, one can potentially titrate the dosing of two drugs in their respective therapeutic windows to limit toxicity based on patient-to-patient differences. Such toxicity-based adjustments in dual-payload ADC administration can be more difficult since the therapeutic window of these is often a bit smaller,” he adds.